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CNRS research engineer (IR0)
Key Words
- MR spectroscopy
- Chemical shift imaging
- Post processing

Current Research Interest and projects



Journal Article

  • Chatel, B, Hourdé, C, Gondin, J, Fouré, A, Le Fur, Y, Vilmen, C, Bernard, M, Messonnier, LA & Bendahan, D 2017, “Impaired muscle force production and higher fatigability in a mouse model of sickle cell disease”, Blood Cells, Molecules & Diseases, vol. 63, p. 37-44.
    Résumé : Skeletal muscle function has been scarcely investigated in sickle cell disease (SCD) so that the corresponding impact of sickle hemoglobin is still a matter of debate. The purpose of this study was to investigate muscle force production and fatigability in SCD and to identify whether exercise intensity could have a modulatory effect. Ten homozygous sickle cell (HbSS), ten control (HbAA) and ten heterozygous (HbAS) mice were submitted to two stimulation protocols (moderate and intense) to assess force production and fatigability. We showed that specific maximal tetanic force was lower in HbSS mice as compared to other groups. At the onset of the stimulation period, peak force was reduced in HbSS and HbAS mice as compared to HbAA mice. Contrary to the moderate protocol, the intense stimulation protocol was associated with a larger decrease in peak force and rate of force development in HbSS mice as compared to HbAA and HbAS mice. These findings provide in vivo evidence of impaired muscle force production and resistance to fatigue in SCD. These changes are independent of muscle mass. Moreover, SCD is associated with muscle fatigability when exercise intensity is high.
    Mots-clés : crmbm, Exercise intensity, msk, Muscle mass, Muscle volume, Rate of force development.

  • Donadieu, M, Le Fur, Y, Maarouf, A, Gherib, S, Ridley, B, Pini, L, Rapacchi, S, Confort-Gouny, S, Guye, M, Schad, LR, Maudsley, AA, Pelletier, J, Audoin, B, Zaaraoui, W & Ranjeva, J-P 2017, “Metabolic counterparts of sodium accumulation in multiple sclerosis: A whole brain (23)Na-MRI and fast (1)H-MRSI study”, Multiple Sclerosis (Houndmills, Basingstoke, England), p. 1352458517736146.
    Résumé : BACKGROUND: Increase of brain total sodium concentrations (TSC) is present in multiple sclerosis (MS), but its pathological involvement has not been assessed yet. OBJECTIVE: To determine in vivo the metabolic counterpart of brain sodium accumulation. MATERIALS/METHODS: Whole brain (23)Na-MR imaging and 3D-(1)H-EPSI data were collected in 21 relapsing-remitting multiple sclerosis (RRMS) patients and 20 volunteers. Metabolites and sodium levels were extracted from several regions of grey matter (GM), normal-appearing white matter (NAWM) and white matter (WM) T2 lesions. Metabolic and ionic levels expressed as Z-scores have been averaged over the different compartments and used to explain sodium accumulations through stepwise regression models. RESULTS: MS patients showed significant (23)Na accumulations with lower choline and glutamate-glutamine (Glx) levels in GM; (23)Na accumulations with lower N-acetyl aspartate (NAA), Glx levels and higher Myo-Inositol (m-Ins) in NAWM; and higher (23)Na, m-Ins levels with lower NAA in WM T2 lesions. Regression models showed associations of TSC increase with reduced NAA in GM, NAWM and T2 lesions, as well as higher total-creatine, and smaller decrease of m-Ins in T2 lesions. GM Glx levels were associated with clinical scores. CONCLUSION: Increase of TSC in RRMS is mainly related to neuronal mitochondrial dysfunction while dysfunction of neuro-glial interactions within GM is linked to clinical scores.
    Mots-clés : 23Na-MRI, crmbm, demyelination, MRSI, Multiple sclerosis, neurodegeneration, snc, stepwise regression.

  • Leporq, B, Troter, AL, Fur, YL, Salort-Campana, E, Guye, M, Beuf, O, Attarian, S & Bendahan, D 2017, “Combined quantification of fatty infiltration, T1-relaxation times and T2*-relaxation times in normal-appearing skeletal muscle of controls and dystrophic patients”, Magnetic Resonance Materials in Physics, Biology and Medicine, vol. 30, no. 4, p. 407-415, viewed 18August,2017, .
    Résumé : ObjectivesTo evaluate the combination of a fat–water separation method with an automated segmentation algorithm to quantify the intermuscular fatty-infiltrated fraction, the relaxation times, and the microscopic fatty infiltration in the normal-appearing muscle.Materials and methodsMR acquisitions were performed at 1.5T in seven patients with facio-scapulo-humeral dystrophy and eight controls. Disease severity was assessed using commonly used scales for the upper and lower limbs. The fat–water separation method provided proton density fat fraction (PDFF) and relaxation times maps (T2* and T1). The segmentation algorithm distinguished adipose tissue and normal-appearing muscle from the T2* map and combined active contours, a clustering analysis, and a morphological closing process to calculate the index of fatty infiltration (IFI) in the muscle compartment defined as the relative amount of pixels with the ratio between the number of pixels within IMAT and the total number of pixels (IMAT + normal appearing muscle).ResultsIn patients, relaxation times were longer and a larger fatty infiltration has been quantified in the normal-appearing muscle. T2* and PDFF distributions were broader. The relaxation times were correlated to the Vignos scale whereas the microscopic fatty infiltration was linked to the Medwin-Gardner-Walton scale. The IFI was linked to a composite clinical severity scale gathering the whole set of scales.ConclusionThe MRI indices quantified within the normal-appearing muscle could be considered as potential biomarkers of dystrophies and quantitatively illustrate tissue alterations such as inflammation and fatty infiltration.
    Mots-clés : crmbm, Magnetic Resonance Imaging, msk, Muscle dystrophies, Segmentation.


Journal Article

  • Béchir, N, Pecchi, E, Vilmen, C, Le Fur, Y, Amthor, H, Bernard, M, Bendahan, D & Giannesini, B 2016, “ActRIIB blockade increases force-generating capacity and preserves energy supply in exercising mdx mouse muscle in vivo”, FASEB journal: official publication of the Federation of American Societies for Experimental Biology, vol. 30, no. 10, p. 3551-3562.
    Résumé : Postnatal blockade of the activin type IIB receptor (ActRIIB) represents a promising therapeutic strategy for counteracting dystrophic muscle wasting. However, its impact on muscle function and bioenergetics remains poorly documented in physiologic conditions. We have investigated totally noninvasively the effect of 8-wk administration of either soluble ActRIIB signaling inhibitor (sActRIIB-Fc) or vehicle PBS (control) on gastrocnemius muscle force-generating capacity, energy metabolism, and anatomy in dystrophic mdx mice using magnetic resonance (MR) imaging and dynamic [(31)P]-MR spectroscopy ([(31)P]-MRS) in vivo ActRIIB inhibition increased muscle volume (+33%) without changing fiber-type distribution, and increased basal animal oxygen consumption (+22%) and energy expenditure (+23%). During an in vivo standardized fatiguing exercise, maximum and total absolute contractile forces were larger (+40 and 24%, respectively) in sActRIIB-Fc treated animals, whereas specific force-generating capacity and fatigue resistance remained unaffected. Furthermore, sActRIIB-Fc administration did not alter metabolic fluxes, ATP homeostasis, or contractile efficiency during the fatiguing bout of exercise, although it dramatically reduced the intrinsic mitochondrial capacity for producing ATP. Overall, sActRIIB-Fc treatment increased muscle mass and strength without altering the fundamental weakness characteristic of dystrophic mdx muscle. These data support the clinical interest of ActRIIB blockade for reversing dystrophic muscle wasting.-Béchir, N., Pecchi, E., Vilmen, C., Le Fur, Y., Amthor, H., Bernard, M., Bendahan, D., Giannesini, B. ActRIIB blockade increases force-generating capacity and preserves energy supply in exercising mdx mouse muscle in vivo.
    Mots-clés : crmbm, Duchenne muscular dystrophy, msk, Muscle Fatigue, myostatin inhibition, skeletal muscle hypertrophy.

  • Donadieu, M, Le Fur, Y, Confort-Gouny, S, Le Troter, A, Guye, M & Ranjeva, J-P 2016, “Evidencing different neurochemical profiles between thalamic nuclei using high resolution 2D-PRESS semi-LASER (1)H-MRSI at 7 T”, Magma (New York, N.Y.), vol. 29, no. 3, p. 491-501.
    Résumé : OBJECTIVE: To demonstrate that high resolution (1)H semi-LASER MRSI acquired at 7 T permits discrimination of metabolic patterns of different thalamic nuclei. MATERIALS AND METHODS: Thirteen right-handed healthy volunteers were explored at 7 T using a high-resolution 2D-semi-LASER (1)H-MRSI sequence to determine the relative levels of N-Acetyl Aspartate (NAA), choline (Cho) and creatine-phosphocreatine (Cr) in eight VOIs (volume <0.3 ml) centered on four different thalamic nuclei located on the Oxford thalamic connectivity atlas. Post-processing was done using the CSIAPO software. Chemical shift displacement of metabolites was evaluated on a phantom and correction factors were applied to in vivo data. RESULTS: The global assessment (ANOVA p < 0.05) of the neurochemical profiles (NAA, Cho and Cr levels) with thalamic nuclei and hemispheres as factors showed a significant global effect (F = 11.98, p < 0.0001), with significant effect of nucleus type (p < 0.0001) and hemisphere (p < 0.0001). Post hoc analyses showed differences in neurochemical profiles between the left and the right hemisphere (p < 0.05), and differences in neurochemical profiles between nuclei within each hemisphere (p < 0.05). CONCLUSION: For the first time, using high resolution 2D-PRESS semi-LASER (1)H-MRSI acquired at 7 T, we demonstrated that the neurochemical profiles were different between thalamic nuclei, and that these profiles were dependent on the brain hemisphere.
    Mots-clés : 1H-MRSI, Adult, Analysis of Variance, Aspartic Acid, Brain, Choline, Connectivity atlas, Creatine, crmbm, Female, Healthy Volunteers, Humans, Lasers, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Male, Neurochemical profiles, Neurodegenerative Diseases, Phantoms, Imaging, Phosphocreatine, snc, Software, Spectrophotometry, Thalamic nuclei, Thalamus, Ultra high field, Young Adult.

  • Donadieu, M, Le Fur, Y, Lecocq, A, Maudsley, AA, Gherib, S, Soulier, E, Confort-Gouny, S, Pariollaud, F, Ranjeva, M-P, Pelletier, J, Guye, M, Zaaraoui, W, Audoin, B & Ranjeva, J-P 2016, “Metabolic voxel-based analysis of the complete human brain using fast 3D-MRSI: Proof of concept in multiple sclerosis”, Journal of magnetic resonance imaging: JMRI, vol. 44, no. 2, p. 411-419.
    Résumé : PURPOSE: To detect local metabolic abnormalities over the complete human brain in multiple sclerosis (MS) patients, we used optimized fast volumic echo planar spectroscopic imaging (3D-EPSI). MATERIALS AND METHODS: Weighted mean combination of two 3D-EPSI covering the whole brain acquired at 3T in AC-PC and AC-PC+15° axial planes was performed to obtain high-quality metabolite maps for five metabolites: N-acetyl aspartate (NAA), glutamate+glutamine (Glx), choline (Cho), myo-inositol (m-Ins), and creatine+phosphocreatine (tCr). After spatial normalization, maps from 19 patients suffering from relapsing-remitting MS were compared to 19 matched controls using statistical mapping analyses to determine the topography of metabolic abnormalities. Probabilistic white matter (WM) T2 lesion maps and gray matter (GM) atrophy maps were also generated. RESULTS: Two-group analysis of variance (ANOVA) (SPM8, P < 0.005, false discovery rate [FDR]-corrected P < 0.05 at the cluster level with age and sex as confounding covariates) comparing patients and controls matched for age and sex showed clusters of abnormal metabolite levels with 1) decreased NAA (around -15%) and Glx (around 20%) predominantly in GM within prefrontal cortices, motor cortices, bilateral thalami, and mesial temporal cortices in line with neuronal/neuro-astrocytic dysfunction; 2) increased m-Ins (around + 20%) inside WM T2 lesions and in the normal-appearing WM of temporal-occipital lobes, suggesting glial activation. CONCLUSION: We demonstrate the ability to noninvasively map over the complete brain-from vertex to cerebellum-with a validated sequence, the metabolic abnormalities associated with MS, for characterizing the topography of pathological processes affecting widespread areas of WM and GM and its functional impact. J. Magn. Reson. Imaging 2016;44:411-419.

  • Dutour, A, Abdesselam, I, Ancel, P, Kober, F, Mrad, G, Darmon, P, Ronsin, O, Pradel, V, Lesavre, N, Martin, JC, Jacquier, A, Lefur, Y, Bernard, M & Gaborit, B 2016, “Exenatide decreases liver fat content and epicardial adipose tissue in patients with obesity and type 2 diabetes: a prospective randomized clinical trial using magnetic resonance imaging and spectroscopy”, Diabetes, Obesity & Metabolism, vol. 18, no. 9, p. 882-891.
    Résumé : AIM: To conduct a prospective randomized trial to investigate the effect of glucagon-like peptide-1 (GLP-1) analogues on ectopic fat stores. METHODS: A total of 44 obese subjects with type 2 diabetes uncontrolled on oral antidiabetic drugs were randomly assigned to receive exenatide or reference treatment according to French guidelines. Epicardial adipose tissue (EAT), myocardial triglyceride content (MTGC), hepatic triglyceride content (HTGC) and pancreatic triglyceride content (PTGC) were assessed 45 min after a standardized meal with 3T magnetic resonance imaging and proton magnetic resonance spectroscopy before and after 26 weeks of treatment. RESULTS: The study population had a mean glycated haemoglobin (HbA1c) level of 7.5 ± 0.2% and a mean body mass index of 36.1 ± 1.1 kg/m(2) . Ninety five percent had hepatic steatosis at baseline (HTGC ≥ 5.6%). Exenatide and reference treatment led to a similar improvement in HbA1c (-0.7 ± 0.3% vs. -0.7 ± 0.4%; p = 0.29), whereas significant weight loss was observed only in the exenatide group (-5.5 ± 1.2 kg vs. -0.2 ± 0.8 kg; p = 0.001 for the difference between groups). Exenatide induced a significant reduction in EAT (-8.8 ± 2.1%) and HTGC (-23.8 ± 9.5%), compared with the reference treatment (EAT: -1.2 ± 1.6%, p = 0.003; HTGC: +12.5 ± 9.6%, p = 0.007). No significant difference was observed in other ectopic fat stores, PTGC or MTGC. In the group treated with exenatide, reductions in liver fat and EAT were not associated with homeostatic model assessment of insulin resistance index, adiponectin, HbA1c or fructosamin change, but were significantly related to weight loss (r = 0.47, p = 0.03, and r = 0.50, p = 0.018, respectively). CONCLUSION: Our data indicate that exenatide is an effective treatment to reduce liver fat content and epicardial fat in obese patients with type 2 diabetes, and these effects are mainly weight loss dependent.
    Mots-clés : crmbm, cvs, epicardial adipose tissue, glucagon-like peptide 1 receptor agonist, hepatic triglyceride content, Magnetic Resonance Imaging, magnetic-resonance imaging, myocardial triglyceride content, Obesity, pancreatic triglyceride content, Proton Magnetic Resonance Spectroscopy, proton magnetic-resonance spectroscopy, type 2 diabetes.

  • Fouré, A, Nosaka, K, Gastaldi, M, Mattei, J-P, Boudinet, H, Guye, M, Vilmen, C, Le Fur, Y, Bendahan, D & Gondin, J 2016, “Effects of branched-chain amino acids supplementation on both plasma amino acids concentration and muscle energetics changes resulting from muscle damage: A randomized placebo controlled trial”, Clinical Nutrition (Edinburgh, Scotland), vol. 35, no. 1, p. 83-94.
    Résumé : BACKGROUND & AIMS: Branched-chain amino acids promote muscle-protein synthesis, reduce protein oxidation and have positive effects on mitochondrial biogenesis and reactive oxygen species scavenging. The purpose of the study was to determine the potential benefits of branched-chain amino acids supplementation on changes in force capacities, plasma amino acids concentration and muscle metabolic alterations after exercise-induced muscle damage. METHODS: (31)P magnetic resonance spectroscopy and biochemical analyses were used to follow the changes after such damage. Twenty six young healthy men were randomly assigned to supplemented branched-chain amino acids or placebo group. Knee extensors maximal voluntary isometric force was assessed before and on four days following exercise-induced muscle damage. Concentrations in phosphocreatine [PCr], inorganic phosphate [Pi] and pH were measured during a standardized rest-exercise-recovery protocol before, two (D2) and four (D4) days after exercise-induced muscle damage. RESULTS: No significant difference between groups was found for changes in maximal voluntary isometric force (-24% at D2 and -21% at D4). Plasma alanine concentration significantly increased immediately after exercise-induced muscle damage (+25%) in both groups while concentrations in glycine, histidine, phenylalanine and tyrosine decreased. No difference between groups was found in the increased resting [Pi] (+42% at D2 and +34% at D4), decreased resting pH (-0.04 at D2 and -0.03 at D4) and the slower PCr recovery rate (-18% at D2 and -24% at D4). CONCLUSIONS: The damaged muscle was not able to get benefits out of the increased plasma branched-chain amino acids availability to attenuate changes in indirect markers of muscle damage and muscle metabolic alterations following exercise-induced muscle damage.
    Mots-clés : crmbm, Double blind randomized placebo controlled trial, Exercise induced-muscle damage, Magnetic Resonance Spectroscopy, msk.

  • Layec, G, Bringard, A, LE Fur, Y, Micallef, J-P, Vilmen, C, Perrey, S, Cozzone, PJ & Bendahan, D 2016, “Mitochondrial Coupling and Contractile Efficiency in Humans with High and Low V˙O2peaks”, Medicine and Science in Sports and Exercise, vol. 48, no. 5, p. 811-821.
    Résumé : INTRODUCTION: Endurance training elicits tremendous adaptations of the mitochondrial energetic capacity. Yet, the effects of training or physical fitness on mitochondrial efficiency during exercise are still unclear. Accordingly, the purpose of the present study was to examine in vivo the differences in mitochondrial efficiency and ATP cost of contraction during exercise in two groups of adults differing in their aerobic capacity. METHOD: We simultaneously assessed the ATP synthesis and O2 fluxes with P-magnetic resonance spectroscopy and pulmonary gas exchange measurements in seven endurance-trained (ET, V˙O2max: 67 ± 8 mL·min·kg) and seven recreationally active (RA, V˙O2max: 43 ± 7 mL·min·kg) subjects during 6 min of dynamic moderate-intensity knee extension. RESULTS: The ATP cost of dynamic contraction was not significantly different between ET and RA (P > 0.05). Similarly, end-exercise O2 consumption was not significantly different between groups (ET: 848 ± 155 mL·min and RA: 760 ± 131 mL·min, P > 0.05). During the recovery period, the PCr offset time constant was significantly faster in ET compared with RA (ET: 32 ± 8 s and RA: 43 ± 10 s, P < 0.05), thus indicating an increased mitochondrial capacity for ATP synthesis in the quadriceps of ET. In contrast, the estimated mitochondrial efficiency during exercise was not significantly different (P/O, ET: 2.0 ± 1.0 and RA: 1.8 ± 0.4, P > 0.05). Consequently, the higher mitochondrial capacity for ATP synthesis in ET likely originated from an elevated mitochondrial volume density, mitochondria-specific respiratory capacity, and/or slower postexercise inactivation of oxidative phosphorylation by the parallel activation mechanism. CONCLUSION: Together, these findings reveal that 1) mitochondrial and contractile efficiencies are unaltered by several years of endurance training in young adults, and 2) the training-induced improvement in mitochondrial energetic capacity appears to be independent from changes in mitochondrial coupling.
    Mots-clés : crmbm, msk.

  • Layec, G, Gifford, JR, Trinity, JD, Hart, CR, Garten, RS, Park, SY, Le Fur, Y, Jeong, E-K & Richardson, RS 2016, “Accuracy and precision of quantitative 31P-MRS measurements of human skeletal muscle mitochondrial function”, American Journal of Physiology. Endocrinology and Metabolism, vol. 311, no. 2, p. E358-366.
    Résumé : Although theoretically sound, the accuracy and precision of (31)P-magnetic resonance spectroscopy ((31)P-MRS) approaches to quantitatively estimate mitochondrial capacity are not well documented. Therefore, employing four differing models of respiratory control [linear, kinetic, and multipoint adenosine diphosphate (ADP) and phosphorylation potential], this study sought to determine the accuracy and precision of (31)P-MRS assessments of peak mitochondrial adenosine-triphosphate (ATP) synthesis rate utilizing directly measured peak respiration (State 3) in permeabilized skeletal muscle fibers. In 23 subjects of different fitness levels, (31)P-MRS during a 24-s maximal isometric knee extension and high-resolution respirometry in muscle fibers from the vastus lateralis was performed. Although significantly correlated with State 3 respiration (r = 0.72), both the linear (45 ± 13 mM/min) and phosphorylation potential (47 ± 16 mM/min) models grossly overestimated the calculated in vitro peak ATP synthesis rate (P < 0.05). Of the ADP models, the kinetic model was well correlated with State 3 respiration (r = 0.72, P < 0.05), but moderately overestimated ATP synthesis rate (P < 0.05), while the multipoint model, although being somewhat less well correlated with State 3 respiration (r = 0.55, P < 0.05), most accurately reflected peak ATP synthesis rate. Of note, the PCr recovery time constant (τ), a qualitative index of mitochondrial capacity, exhibited the strongest correlation with State 3 respiration (r = 0.80, P < 0.05). Therefore, this study reveals that each of the (31)P-MRS data analyses, including PCr τ, exhibit precision in terms of mitochondrial capacity. As only the multipoint ADP model did not overstimate the peak skeletal muscle mitochondrial ATP synthesis, the multipoint ADP model is the only quantitative approach to exhibit both accuracy and precision.

  • Layec, G, Trinity, JD, Hart, CR, Le Fur, Y, Sorensen, JR, Jeong, E-K & Richardson, RS 2016, “Evidence of a metabolic reserve in the skeletal muscle of elderly people”, Aging, vol. 9, no. 1, p. 52-67.
    Résumé : The purpose of the present study was to determine whether mitochondrial function is limited by O2 availability or the intrinsic capacity of mitochondria to synthesize ATP in elderly individuals. To this aim, we examined, in comparison to free-flow conditions (FF), the effect of superimposing reactive hyperemia (RH), induced by a period of brief ischemia during the last min of exercise, on O2 availability and mitochondrial function in the calf muscle. 12 healthy, untrained, elderly subjects performed dynamic plantar flexion exercise and phosphorus magnetic resonance spectroscopy (31P-MRS), near-infrared spectroscopy (NIRS), and Doppler ultrasound were used to assess muscle metabolism and peripheral hemodynamics. Limb blood flow [area under the curve (AUC), FF: 1.5±0.5L; RH: 3.2±1.1L, P<0.01] and convective O2 delivery (AUC, FF: 0.30±0.13L; RH: 0.64±0.29L, P<0.01) were significantly increased in RH in comparison to FF. RH was also associated with significantly higher capillary blood flow (P<0.05) and this resulted in a 33% increase in estimated peak mitochondrial ATP synthesis rate (FF: 24±11 mM.min-1; RH: 31±7 mM.min-1, P<0.05). These results document a hemodynamic reserve in the contracting calf muscle of the elderly accessible by superimposing reactive hyperemia. Furthermore, this increase in O2 availability enhanced mitochondrial function thus indicating a skeletal muscle metabolic reserve despite advancing age and low level of physical activity.

  • Martin, A, Grosprêtre, S, Vilmen, C, Guye, M, Mattei, J-P, LE Fur, Y, Bendahan, D & Gondin, J 2016, “The Etiology of Muscle Fatigue Differs between Two Electrical Stimulation Protocols”, Medicine and Science in Sports and Exercise, vol. 48, no. 8, p. 1474-1484.
    Résumé : PURPOSE: This study aimed at investigating the mechanisms involved in the force reduction induced by two electrical stimulation (ES) protocols that were designed to activate motor units differently. METHODS: The triceps surae of 11 healthy subjects (8 men; age, ~28 yr) was activated using ES applied over the tibial nerve. Two ES protocols (conventional [CONV]: 20 Hz, 0.05 ms vs wide-pulse high-frequency [WPHF]: 80 Hz, 1 ms) were performed and involved 40 trains (6 s on-6 s off) delivered at an intensity (IES) evoking 20% of maximal voluntary contraction. To analyze the mechanical properties of the motor units activated at IES, force-frequency relation was evoked before and after each protocol. H-reflex and M-wave responses evoked by the last stimulation pulse were also assessed during each ES protocol. Electromyographic responses (∑EMG) were recorded after each train to analyze the behavior of the motor units activated at IES. Metabolic variables, including relative concentrations of phosphocreatine and inorganic phosphate as well as intracellular pH, were assessed using P-MR spectroscopy during each protocol. RESULTS: Larger H-reflex amplitudes were observed during WPHF as compared with CONV, whereas opposite findings were observed for M-wave amplitudes. Despite this difference, both the force reduction (-26%) and metabolic changes were similar between the two protocols. The CONV protocol induced a rightward shift of the force-frequency relation, whereas a significant reduction of the ∑EMG evoked at IES was observed only for the WPHF. CONCLUSIONS: These results suggest that a decreased number of active motor units mainly contributed to WPHF-induced force decrease, whereas intracellular processes were most likely involved in the force reduction occurring during CONV stimulation.
    Mots-clés : crmbm, msk.

  • Sdika, M, Tonson, A, Le Fur, Y, Cozzone, PJ & Bendahan, D 2016, “Multi-atlas-based fully automatic segmentation of individual muscles in rat leg”, Magma (New York, N.Y.), vol. 29, no. 2, p. 223-235.
    Résumé : OBJECTIVE: To quantify individual muscle volume in rat leg MR images using a fully automatic multi-atlas-based segmentation method. MATERIALS AND METHODS: We optimized a multi-atlas-based segmentation method to take into account the voxel anisotropy of numbers of MRI acquisition protocols. We mainly tested an image upsampling process along Z and a constraint on the nonlinear deformation in the XY plane. We also evaluated a weighted vote procedure and an original implementation of an artificial atlas addition. Using this approach, we measured gastrocnemius and plantaris muscle volumes and compared the results with manual segmentation. The method reliability for volume quantification was evaluated using the relative overlap index. RESULTS: The most accurate segmentation was obtained using a nonlinear registration constrained in the XY plane by zeroing the Z component of the displacement and a weighted vote procedure for both muscles regardless of the number of atlases. The performance of the automatic segmentation and the corresponding volume quantification outperformed the interoperator variability using a minimum of three original atlases. CONCLUSION: We demonstrated the reliability of a multi-atlas segmentation approach for the automatic segmentation and volume quantification of individual muscles in rat leg and found that constraining the registration in plane significantly improved the results.
    Mots-clés : Anisotropy, crmbm, Magnetic Resonance Imaging, msk, Multi-atlas, rat, Reproducibility of Results, Segmentation, skeletal muscle.


Journal Article

  • Fouré, A, Wegrzyk, J, LE Fur, Y, Mattei, J-P, Boudinet, H, Vilmen, C, Bendahan, D & Gondin, J 2015, “Impaired mitochondrial function and reduced energy cost as a result of muscle damage”, Medicine and Science in Sports and Exercise, vol. 47, no. 6, p. 1135-1144.
    Résumé : PURPOSE: Although it has been largely acknowledged that isometric neuromuscular electrostimulation (NMES) exercise induces larger muscle damage than voluntary contractions, the corresponding effects on muscle energetics remain to be determined. Voluntary exercise-induced muscle damage (EIMD) has been reported to have minor slight effects on muscle metabolic response to subsequent dynamic exercise, but the magnitude of muscle energetics alterations for NMES EIMD has never been documented. METHODS: P magnetic resonance spectroscopy measurements were performed in 13 young healthy males during a standardized rest-exercise-recovery protocol before (D0) and 2 d (D2) and 4 d (D4) after NMES EIMD on knee extensor muscles. Changes in kinetics of phosphorylated metabolite concentrations (i.e., phosphocreatine [PCr], inorganic phosphate [Pi], and adenosine triphosphate [ATP]) and pH were assessed to investigate aerobic and anaerobic rates of ATP production and energy cost of contraction (Ec). RESULTS: Resting [Pi]/[PCr] ratio increased at D2 (+39%) and D4 (+29%), mainly owing to the increased [Pi] (+43% and +32%, respectively), whereas a significant decrease in resting pH was determined (-0.04 pH unit and -0.03 pH unit, respectively). PCr recovery rate decreased at D2 (-21%) and D4 (-23%) in conjunction with a significantly decreased total rate of ATP production at D4 (-18%) mainly owing to an altered aerobic ATP production (-19%). Paradoxically, Ec was decreased at D4 (-21%). CONCLUSION: Overall, NMES EIMD led to intramuscular acidosis in resting muscle and mitochondrial impairment in exercising muscle. Alterations of noncontractile processes and/or adaptive mechanisms to muscle damage might account for the decreased Ec during the dynamic exercise.
    Mots-clés : crmbm, msk.

  • Jubeau, M, LE Fur, Y, Duhamel, G, Wegrzyk, J, Confort-Gouny, S, Vilmen, C, Cozzone, PJ, Mattei, JP, Bendahan, D & Gondin, J 2015, “Localized metabolic and t2 changes induced by voluntary and evoked contractions”, Medicine and Science in Sports and Exercise, vol. 47, no. 5, p. 921-930.
    Résumé : PURPOSE: This study compared the metabolic and activation changes induced by electrically evoked (neuromuscular electrical stimulation (NMES)) and voluntary (VOL) contractions performed at the same submaximal intensity using P chemical shift imaging (CSI) and T2 mapping investigations. METHODS: Fifteen healthy subjects were asked to perform both NMES and VOL protocols with the knee extensors (i.e., 232 isometric contractions at 30% of maximal force) inside a 3-T scanner for two experimental sessions. During the first session, metabolic variations, i.e., phosphocreatine (PCr), inorganic phosphate (Pi), and pH, were recorded using localized P CSI. During a second session, T2 maps of the knee extensors were obtained at rest and immediately after each exercise. Voxels of interest were selected from the directly stimulated vastus lateralis and from the nondirectly stimulated rectus femoris/vastus intermedius muscles. RESULTS: PCr depletion recorded throughout the NMES session was significantly larger in the vastus lateralis as compared with the rectus femoris/vastus intermedius muscles for both conditions (VOL and NMES). A higher occurrence of Pi splitting and a greater acidosis was found during NMES as compared with VOL exercise, illustrating the heterogeneous activation of both slow and fast muscle fibers. T2 changes were greater after NMES as compared with VOL for both muscles but were not necessarily related to the localized metabolic demand. CONCLUSION: We provided direct evidence that the metabolic demand was strongly related to both the exercise modality and the site of stimulation. On the basis of the occurrence of Pi splitting, we suggested that NMES can activate fast muscle fibers even at low force levels.
    Mots-clés : crmbm, msk.

  • Layec, G, Bringard, A, Le Fur, Y, Micallef, J-P, Vilmen, C, Perrey, S, Cozzone, PJ & Bendahan, D 2015, “Opposite effects of hyperoxia on mitochondrial and contractile efficiency in human quadriceps muscles”, American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, vol. 308, no. 8, p. R724-733.
    Résumé : Exercise efficiency is an important determinant of exercise capacity. However, little is known about the physiological factors that can modulate muscle efficiency during exercise. We examined whether improved O2 availability would 1) impair mitochondrial efficiency and shift the energy production toward aerobic ATP synthesis and 2) reduce the ATP cost of dynamic contraction owing to an improved neuromuscular efficiency, such that 3) whole body O2 cost would remain unchanged. We used (31)P-magnetic resonance spectroscopy, surface electromyography, and pulmonary O2 consumption (V̇o2p) measurements in eight active subjects during 6 min of dynamic knee-extension exercise under different fractions of inspired O2 (FiO2 , 0.21 in normoxia and 1.0 in hyperoxia). V̇o2p (755 ± 111 ml/min in normoxia and 799 ± 188 ml/min in hyperoxia, P > 0.05) and O2 cost (P > 0.05) were not significantly different between normoxia and hyperoxia. In contrast, the total ATP synthesis rate and the ATP cost of dynamic contraction were significantly lower in hyperoxia than normoxia (P < 0.05). As a result, the ratio of the rate of oxidative ATP synthesis from the quadriceps to V̇o2p was lower in hyperoxia than normoxia but did not reach statistical significance (16 ± 3 mM/ml in normoxia and 12 ± 5 mM/ml in hyperoxia, P = 0.07). Together, these findings reveal dynamic and independent regulations of mitochondrial and contractile efficiency as a consequence of O2 availability in young active individuals. Furthermore, muscle efficiency appears to be already optimized in normoxia and is unlikely to contribute to the well-established improvement in exercise capacity induced by hyperoxia.
    Mots-clés : 31P-magnetic resonance spectroscopy, Adenosine Triphosphate, Adult, Bicycling, crmbm, Electromyography, Energy Metabolism, Exercise, Exercise Tolerance, Female, Humans, Hydrogen-Ion Concentration, Hyperoxia, Isometric Contraction, Lung, Magnetic Resonance Spectroscopy, Male, Mitochondria, Mitochondria, Muscle, msk, muscle efficiency, Muscle energetics, Muscle Fatigue, Muscle Strength, O2 availability, Oxygen Consumption, Quadriceps Muscle, Time Factors.

  • Layec, G, Hart, CR, Trinity, JD, Le Fur, Y, Jeong, E-K & Richardson, RS 2015, “Skeletal muscle work efficiency with age: the role of non-contractile processes.”, Clinical science (London, England : 1979), vol. 128, no. 3, p. 213-23.
    Résumé : Although skeletal muscle work efficiency probably plays a key role in limiting mobility of the elderly, the physiological mechanisms responsible for this diminished function remain incompletely understood. Thus, in the quadriceps of young (n=9) and old (n=10) subjects, we measured the cost of muscle contraction (ATP cost) with 31P-magnetic resonance spectroscopy (31P-MRS) during (i) maximal intermittent contractions to elicit a metabolic demand from both cross-bridge cycling and ion pumping and (ii) a continuous maximal contraction to predominantly tax cross-bridge cycling. The ATP cost of the intermittent contractions was significantly greater in the old (0.30±0.22mM·min-1·N·m-1) compared with the young (0.13±0.03mM·min-1·N·m-1, P<0.05). In contrast, at the end of the continuous contraction protocol, the ATP cost in the old (0.10±0.07mM·min-1·N·m-1) was not different from the young (0.06±0.02mM·min-1·N·m-1, P=0.2). In addition, the ATP cost of the intermittent contractions correlated significantly with the single leg peak power of the knee-extensors assessed during incremental dynamic exercise (r=-0.55; P<0.05). Overall, this study reveals an age-related increase in the ATP cost of contraction, probably mediated by an excessive energy demand from ion pumping, which probably contributes to both the decline in muscle efficiency and functional capacity associated with aging.
    Mots-clés : msk.

  • Le Fur, Y & Cozzone, PJ 2015, “Hemi-spectrum substitution after water signal fitting (HESWAF): an improvement of the modulus post-processing of MR spectra”, Magma (New York, N.Y.), vol. 28, no. 1, p. 67-85.
    Résumé : OBJECTIVE: In a previous study, we have shown that modulus post-processing is a simple and efficient tool to both phase correct and frequency align magnetic resonance (MR) spectra automatically. Furthermore, this technique also eliminates sidebands and phase distortions. The advantages of the modulus technique have been illustrated in several applications to brain proton MR spectroscopy. Two possible drawbacks have also been pointed out. The first one is the theoretical decrease in signal-to-noise ratio (SNR) by a factor up to √2 when comparing the spectrum obtained after modulus versus conventional post-processing. The second pitfall results from the symmetrization of the spectrum induced by modulus post-processing, since any resonance or artifact located at the left of the water resonance is duplicated at the right of the water resonance, thus contaminating the region of the spectrum containing the resonances of interest. Herein, we propose a strategy in order to eliminate these two limitations. MATERIALS AND METHODS: Concerning the SNR issue, two complementary approaches are presented here. The first is based on the application of modulus post-processing before spatial apodization, and the second consists in substituting the left half of the spectrum by the fit of the water resonance before applying modulus post-processing. The symmetrization induced by modulus post-processing then combines the right half of the original spectrum containing the resonances of interest with the left half of the water fit, free of noise and artifacts. Consequently, the SNR is improved when compared to modulus post-processing alone. As a bonus, any artifact or resonance present in the left half of the original spectrum is removed. This solves the second limitation. RESULTS: After validation of the technique on simulations, we demonstrated that this improvement of the modulus technique is significantly advantageous for both in vitro and in vivo applications. CONCLUSION: By improving the SNR of the spectra and eliminating eventual contaminations, the new strategies proposed here confer an additional competitive advantage to the modulus post-processing technique.
    Mots-clés : crmbm, snc.

  • Lecocq, A, Le Fur, Y, Amadon, A, Vignaud, A, Cozzone, PJ, Guye, M & Ranjeva, J-P 2015, “Fast water concentration mapping to normalize (1)H MR spectroscopic imaging”, Magma (New York, N.Y.), vol. 28, no. 1, p. 87-100.
    Résumé : OBJECT: To propose a fast and robust acquisition and post-processing pipeline that is time-compatible with clinical explorations to obtain a proton density (ρ) map used as a reference for metabolic map normalization. This allows inter-subject and inter-group comparisons of magnetic resonance spectroscopic imaging (MRSI) data and longitudinal follow-up for single subjects. MATERIALS AND METHODS: A multi-echo T 2 (*) mapping sequence, the XEP sequence for B 1 (+) -mapping and Driven Equilibrium Single Pulse Observation of T 1-an optimized variable flip angle method for T 1 mapping used for both B 1 (-) -mapping and M 0 calculation-were used to determine correction factors leading to quantitative water proton density maps at 3T. Normalized metabolite maps were obtained on a phantom and nine healthy volunteers. To show the potential use of this technique at the individual level, we also explored one patient with low-grade glioma. RESULTS: Accurate ρ maps were obtained both on phantom and volunteers. After signal normalization with the generated ρ maps, metabolic concentrations determined by the present method differed from theory by <7 % in the phantom and were in agreement with data from the literature for the healthy controls. Using these normalized metabolic values, it was possible to demonstrate in the patient with brain glioma, metabolic abnormalities in normalized N-acetyl aspartate, choline and creatine levels; illustrating the potential for direct use of this technique in clinical studies. CONCLUSION: The proposed combination of sequences provides a robust ρ map that can be used to normalize metabolic maps in clinical MRSI studies.
    Mots-clés : crmbm, snc.

  • Lecocq, A, Le Fur, Y, Maudsley, AA, Le Troter, A, Sheriff, S, Sabati, M, Donadieu, M, Confort-Gouny, S, Cozzone, PJ, Guye, M & Ranjeva, J-P 2015, “Whole-brain quantitative mapping of metabolites using short echo three-dimensional proton MRSI”, Journal of magnetic resonance imaging: JMRI, vol. 42, no. 2, p. 280-289.
    Résumé : BACKGROUND: To improve the extent over which whole brain quantitative three-dimensional (3D) magnetic resonance spectroscopic imaging (MRSI) maps can be obtained and be used to explore brain metabolism in a population of healthy volunteers. METHODS: Two short echo time (20 ms) acquisitions of 3D echo planar spectroscopic imaging at two orientations, one in the anterior commissure-posterior commissure (AC-PC) plane and the second tilted in the AC-PC +15° plane were obtained at 3 Tesla in a group of 10 healthy volunteers. B1 (+) , B1 (-) , and B0 correction procedures and normalization of metabolite signals with quantitative water proton density measurements were performed. A combination of the two spatially normalized 3D-MRSI, using a weighted mean based on the pixel wise standard deviation metabolic maps of each orientation obtained from the whole group, provided metabolite maps for each subject allowing regional metabolic profiles of all parcels of the automated anatomical labeling (AAL) atlas to be obtained. RESULTS: The combined metabolite maps derived from the two acquisitions reduced the regional intersubject variance. The numbers of AAL regions showing N-acetyl aspartate (NAA) SD/Mean ratios lower than 30% increased from 17 in the AC-PC orientation and 41 in the AC-PC+15° orientation, to a value of 76 regions of 116 for the combined NAA maps. Quantitatively, regional differences in absolute metabolite concentrations (mM) over the whole brain were depicted such as in the GM of frontal lobes (cNAA  = 10.03 + 1.71; cCho  = 1.78 ± 0.55; cCr  = 7.29 ± 1.69; cmIns  = 5.30 ± 2.67) and in cerebellum (cNAA  = 5.28 ± 1.77; cCho  = 1.60 ± 0.41; cCr  = 6.95 ± 2.15; cmIns  = 3.60 ± 0.74). CONCLUSION: A double-angulation acquisition enables improved metabolic characterization over a wide volume of the brain. J. Magn. Reson. Imaging 2015;42:280-289.
    Mots-clés : crmbm, snc.

  • Martel, D, Tse Ve Koon, K, Le Fur, Y & Ratiney, H 2015, “Localized 2D COSY sequences: Method and experimental evaluation for a whole metabolite quantification approach”, Journal of Magnetic Resonance (San Diego, Calif.: 1997), vol. 260, p. 98-108.
    Résumé : Two-dimensional spectroscopy offers the possibility to unambiguously distinguish metabolites by spreading out the multiplet structure of J-coupled spin systems into a second dimension. Quantification methods that perform parametric fitting of the 2D MRS signal have recently been proposed for resolved PRESS (JPRESS) but not explicitly for Localized Correlation Spectroscopy (LCOSY). Here, through a whole metabolite quantification approach, correlation spectroscopy quantification performances are studied. The ability to quantify metabolite relaxation constant times is studied for three localized 2D MRS sequences (LCOSY, LCTCOSY and the JPRESS) in vitro on preclinical MR systems. The issues encountered during implementation and quantification strategies are discussed with the help of the Fisher matrix formalism. The described parameterized models enable the computation of the lower bound for error variance - generally known as the Cramér Rao bounds (CRBs), a standard of precision - on the parameters estimated from these 2D MRS signal fittings. LCOSY has a theoretical net signal loss of two per unit of acquisition time compared to JPRESS. A rapid analysis could point that the relative CRBs of LCOSY compared to JPRESS (expressed as a percentage of the concentration values) should be doubled but we show that this is not necessarily true. Finally, the LCOSY quantification procedure has been applied on data acquired in vivo on a mouse brain.
    Mots-clés : snc.

  • Varoquaux, A, le Fur, Y, Imperiale, A, Reyre, A, Montava, M, Fakhry, N, Namer, I-J, Moulin, G, Pacak, K, Guye, M & Taïeb, D 2015, “Magnetic resonance spectroscopy of paragangliomas: new insights into in vivo metabolomics”, Endocrine-Related Cancer, vol. 22, no. 4, p. M1-8.
    Résumé : Paragangliomas (PGLs) can be associated with mutations in genes of the tricarboxylic acid (TCA) cycle. Succinate dehydrogenase (SDHx) mutations are the prime examples of genetically determined TCA cycle defects with accumulation of succinate. Succinate, which acts as an oncometabolite, can be detected by ex vivo metabolomics approaches. The aim of this study was to evaluate the potential role of proton magnetic resonance (MR) spectroscopy ((1)H-MRS) for identifying SDHx-related PGLs in vivo and noninvasively. Eight patients were prospectively evaluated with single voxel (1)H-MRS. MR spectra from eight tumors (four SDHx-related PGLs, two sporadic PGLs, one cervical schwannoma, and one cervical neurofibroma) were acquired and interpreted qualitatively. Compared to other tumors, a succinate resonance peak was detected only in SDHx-related tumor patients. Spectra quality was considered good in three cases, medium in two cases, poor in two cases, and uninterpretable in the latter case. Smaller lesions had lower spectra quality compared to larger lesions. Jugular PGLs also exhibited a poorer spectra quality compared to other locations. (1)H-MRS has always been challenging in terms of its technical requisites. This is even more true for the evaluation of head and neck tumors. However, (1)H-MRS might be added to the classical MR sequences for metabolomic characterization of PGLs. In vivo detection of succinate might guide genetic testing, characterize SDHx variants of unknown significance (in the absence of available tumor sample), and even optimize a selection of appropriate therapies.
    Mots-clés : Adult, Aged, Female, Humans, Male, Metabolomics, Middle Aged, MR-spectroscopy, Paraganglioma, Positron-Emission Tomography, Proton Magnetic Resonance Spectroscopy, snc, Succinate Dehydrogenase, Tumor Burden.

  • Wegrzyk, J, Fouré, A, Le Fur, Y, Maffiuletti, NA, Vilmen, C, Guye, M, Mattei, J-P, Place, N, Bendahan, D & Gondin, J 2015, “Responders to Wide-Pulse, High-Frequency Neuromuscular Electrical Stimulation Show Reduced Metabolic Demand: A 31P-MRS Study in Humans”, PloS One, vol. 10, no. 11, p. e0143972.
    Résumé : Conventional (CONV) neuromuscular electrical stimulation (NMES) (i.e., short pulse duration, low frequencies) induces a higher energetic response as compared to voluntary contractions (VOL). In contrast, wide-pulse, high-frequency (WPHF) NMES might elicit-at least in some subjects (i.e., responders)-a different motor unit recruitment compared to CONV that resembles the physiological muscle activation pattern of VOL. We therefore hypothesized that for these responder subjects, the metabolic demand of WPHF would be lower than CONV and comparable to VOL. 18 healthy subjects performed isometric plantar flexions at 10% of their maximal voluntary contraction force for CONV (25 Hz, 0.05 ms), WPHF (100 Hz, 1 ms) and VOL protocols. For each protocol, force time integral (FTI) was quantified and subjects were classified as responders and non-responders to WPHF based on k-means clustering analysis. Furthermore, a fatigue index based on FTI loss at the end of each protocol compared with the beginning of the protocol was calculated. Phosphocreatine depletion (ΔPCr) was assessed using 31P magnetic resonance spectroscopy. Responders developed four times higher FTI's during WPHF (99 ± 37 ×103 N.s) than non-responders (26 ± 12 ×103 N.s). For both responders and non-responders, CONV was metabolically more demanding than VOL when ΔPCr was expressed relative to the FTI. Only for the responder group, the ∆PCr/FTI ratio of WPHF (0.74 ± 0.19 M/N.s) was significantly lower compared to CONV (1.48 ± 0.46 M/N.s) but similar to VOL (0.65 ± 0.21 M/N.s). Moreover, the fatigue index was not different between WPHF (-16%) and CONV (-25%) for the responders. WPHF could therefore be considered as the less demanding NMES modality-at least in this subgroup of subjects-by possibly exhibiting a muscle activation pattern similar to VOL contractions.
    Mots-clés : crmbm, msk.

  • Yashiro, K, Tonson, A, Pecchi, É, Vilmen, C, Le Fur, Y, Bernard, M, Bendahan, D & Giannesini, B 2015, “Capsiate Supplementation Reduces Oxidative Cost of Contraction in Exercising Mouse Skeletal Muscle In Vivo”, PloS One, vol. 10, no. 6, p. e0128016.
    Résumé : Chronic administration of capsiate is known to accelerate whole-body basal energy metabolism, but the consequences in exercising skeletal muscle remain very poorly documented. In order to clarify this issue, the effect of 2-week daily administration of either vehicle (control) or purified capsiate (at 10- or 100-mg/kg body weight) on skeletal muscle function and energetics were investigated throughout a multidisciplinary approach combining in vivo and in vitro measurements in mice. Mechanical performance and energy metabolism were assessed strictly non-invasively in contracting gastrocnemius muscle using magnetic resonance (MR) imaging and 31-phosphorus MR spectroscopy (31P-MRS). Regardless of the dose, capsiate treatments markedly disturbed basal bioenergetics in vivo including intracellular pH alkalosis and decreased phosphocreatine content. Besides, capsiate administration did affect neither mitochondrial uncoupling protein-3 gene expression nor both basal and maximal oxygen consumption in isolated saponin-permeabilized fibers, but decreased by about twofold the Km of mitochondrial respiration for ADP. During a standardized in vivo fatiguing protocol (6-min of repeated maximal isometric contractions electrically induced at a frequency of 1.7 Hz), both capsiate treatments reduced oxidative cost of contraction by 30-40%, whereas force-generating capacity and fatigability were not changed. Moreover, the rate of phosphocreatine resynthesis during the post-electrostimulation recovery period remained unaffected by capsiate. Both capsiate treatments further promoted muscle mass gain, and the higher dose also reduced body weight gain and abdominal fat content. These findings demonstrate that, in addition to its anti-obesity effect, capsiate supplementation improves oxidative metabolism in exercising muscle, which strengthen this compound as a natural compound for improving health.
    Mots-clés : crmbm, cvs.


Journal Article

  • Gineste, C, Ottenheijm, C, Le Fur, Y, Banzet, S, Pecchi, E, Vilmen, C, Cozzone, PJ, Koulmann, N, Hardeman, EC, Bendahan, D & Gondin, J 2014, “Alterations at the cross-bridge level are associated with a paradoxical gain of muscle function in vivo in a mouse model of nemaline myopathy”, PloS One, vol. 9, no. 9, p. e109066.
    Résumé : Nemaline myopathy is the most common disease entity among non-dystrophic skeletal muscle congenital diseases. The first disease causing mutation (Met9Arg) was identified in the gene encoding α-tropomyosinslow gene (TPM3). Considering the conflicting findings of the previous studies on the transgenic (Tg) mice carrying the TPM3Met9Arg mutation, we investigated carefully the effect of the Met9Arg mutation in 8-9 month-old Tg(TPM3)Met9Arg mice on muscle function using a multiscale methodological approach including skinned muscle fibers analysis and in vivo investigations by magnetic resonance imaging and 31-phosphorus magnetic resonance spectroscopy. While in vitro maximal force production was reduced in Tg(TPM3)Met9Arg mice as compared to controls, in vivo measurements revealed an improved mechanical performance in the transgenic mice as compared to the former. The reduced in vitro muscle force might be related to alterations occuring at the cross-bridges level with muscle-specific underlying mechanisms. In vivo muscle improvement was not associated with any changes in either muscle volume or energy metabolism. Our findings indicate that TPM3(Met9Arg) mutation leads to a mild muscle weakness in vitro related to an alteration at the cross-bridges level and a paradoxical gain of muscle function in vivo. These results clearly point out that in vitro alterations are muscle-dependent and do not necessarily translate into similar changes in vivo.
    Mots-clés : crmbm.

  • Hart, CR, Layec, G, Trinity, JD, Liu, X, Kim, S-E, Groot, HJ, Fur, YL, Sorensen, JR, Jeong, E-K & Richardson, RS 2014, “Evidence of Preserved Oxidative Capacity and Oxygen Delivery in the Plantar Flexor Muscles With Age”, The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, p. glu139, viewed 17September,2014, .
    Résumé : Studies examining the effect of aging on skeletal muscle oxidative capacity have yielded equivocal results; however, these investigations may have been confounded by differences in oxygen (O2) delivery, physical activity, and small numbers of participants. Therefore, we evaluated skeletal muscle oxidative capacity and O2 delivery in a relatively large group (N = 40) of young (22 ± 2 years) and old (73 ± 7 years) participants matched for physical activity. After submaximal dynamic plantar flexion exercise, phosphocreatine (PCr) resynthesis (31P magnetic resonance spectroscopy), muscle reoxygenation (near-infrared spectroscopy), and popliteal artery blood flow (Doppler ultrasound) were measured. The phosphocreatine recovery time constant (Tau) (young: 33 ± 16; old: 30 ± 11 seconds), maximal rate of adenosine triphosphate (ATP) synthesis (young: 25 ± 9; old: 27 ± 8 mM/min), and muscle reoxygenation rates determined by the deoxyhemoglobin/myoglobin recovery Tau (young: 48 ± 5; old: 47 ± 9 seconds) were similar between groups. Similarly, although tending to be higher in the old, there were no significant age-related differences in postexercise popliteal blood flow (area under the curve: young: 1,665 ± 227 vs old: 2,404 ± 357mL, p = .06) and convective O2 delivery (young: 293 ± 146 vs old: 404 ± 191 mL, p = .07). In conclusion, when physical activity and O2 delivery are similar, oxidative capacity in the plantar flexors is not affected by aging. These findings reveal that diminished skeletal muscle oxidative capacity is not an obligatory accompaniment to the aging process.
    Mots-clés : 31P MRS, Aging., Blood Flow, Muscle oxygenation.

  • Kazuya, Y, Tonson, A, Pecchi, E, Dalmasso, C, Vilmen, C, Fur, YL, Bernard, M, Bendahan, D & Giannesini, B 2014, “A single intake of capsiate improves mechanical performance and bioenergetics efficiency in contracting mouse skeletal muscle”, American Journal of Physiology. Endocrinology and Metabolism, vol. 306, no. 10, p. E1110-1119.
    Résumé : Capsiate is known to increase whole body oxygen consumption possibly via the activation of uncoupling processes, but its effect at the skeletal muscle level remains poorly documented and conflicting. To clarify this issue, gastrocnemius muscle function and energetics were investigated in mice 2 h after a single intake of either vehicle (control) or purified capsiate (at 10 or 100 mg/kg body wt) through a multidisciplinary approach combining in vivo and in vitro measurements. Mechanical performance and energy pathway fluxes were assessed strictly noninvasively during a standardized electrostimulation-induced exercise, using an original device implementing 31-phosphorus magnetic resonance spectroscopy, and mitochondrial respiration was evaluated in isolated saponin-permeabilized fibers. Compared with control, both capsiate doses produced quantitatively similar effects at the energy metabolism level, including an about twofold decrease of the mitochondrial respiration sensitivity for ADP. Interestingly, they did not alter either oxidative phosphorylation or uncoupling protein 3 gene expression at rest. During 6 min of maximal repeated isometric contractions, both doses reduced the amount of ATP produced from glycolysis and oxidative phosphorylation but increased the relative contribution of oxidative phosphorylation to total energy turnover (+28 and +21% in the 10- and 100-mg groups, respectively). ATP cost of twitch force generation was further reduced in the 10- (-35%) and 100-mg (-45%) groups. Besides, the highest capsiate dose also increased the twitch force-generating capacity. These data present capsiate as a helpful candidate to enhance both muscle performance and oxidative phosphorylation during exercise, which could constitute a nutritional approach for improving health and preventing obesity and associated metabolic disorders.
    Mots-clés : Animals, Biomechanical Phenomena, Capsaicin, Cells, Cultured, crmbm, Electric Stimulation, Energy Metabolism, Male, Mice, Mice, Inbred C57BL, Muscle Contraction, Muscle, Skeletal, Physical Conditioning, Animal.
    Attachment Full Text PDF 307.6 kb (source)

  • Layec, G, Trinity, JD, Hart, CR, Kim, S-E, Groot, HJ, Le Fur, Y, Sorensen, JR, Jeong, E-K & Richardson, RS 2014, “In vivo evidence of an age-related increase in ATP cost of contraction in the plantar flexor muscles”, Clinical Science (London, England: 1979), vol. 126, no. 8, p. 581-592.
    Résumé : Impaired skeletal muscle efficiency potentially contributes to the age-related decline in exercise capacity and may explain the altered haemodynamic response to exercise in the elderly. Thus we examined whether (i) the ATP cost of contraction increases with age, and (ii) this results in altered convective O(2) delivery to maintain microvascular oxygenation in the calf muscle. To this aim, we used an integrative experimental approach combining (31)P-MRS (magnetic resonance spectroscopy), Doppler ultrasound imaging and NIRS (near-IR spectroscopy) during dynamic plantar flexion exercise at 40% of WR(max) (maximal power output) in 20 healthy young and 20 older subjects matched for physical activity. The ATP cost of contraction was significantly higher in the old (7.2±4.1 mM/min per W) compared with the young (2.4±1.9 mM/min per W; P<0.05) and this was only significantly correlated with the plantar flexion WR(max) value in the old subjects (r=-0.52; P<0.05). Even when differences in power output were taken into account, end-exercise blood flow (old, 259±168 ml/min per W and young, 134±40 ml/min per W; P<0.05) and convective O(2) delivery (old, 0.048±0.031 l/min per W and young, 0.026±0.008 l/min per W; P<0.05) were greater in the old in comparison with the young subjects. In contrast, the NIRS oxyhaemoglobin, deoxyhaemoglobin and microvascular oxygenation indices were not significantly different between the groups (P>0.05). Therefore the present study reveals that, although the peripheral haemodynamic responses to plantar flexion exercise appear to be appropriate, the elevated energy cost of contraction and associated reduction in the WR(max) value in this muscle group may play a role in limiting exercise capacity with age.
    Mots-clés : Adenosine Triphosphate, Aged, Aged, 80 and over, aging, Blood Flow Velocity, Exercise, Female, Hemodynamics, Humans, Magnetic Resonance Spectroscopy, Male, Muscle Contraction, Muscle, Skeletal, Oxygen Consumption, Spectroscopy, Near-Infrared, Ultrasonography, Doppler, Young Adult.

  • Le Fur, Y & Cozzone, PJ 2014, “FID modulus: a simple and efficient technique to phase and align MR spectra”, Magnetic Resonance Materials in Physics, Biology and Medicine, vol. 27, no. 2, p. 131-148, viewed 29October,2014, .
    Résumé : Object The post-processing of MR spectroscopic data requires several steps more or less easy to automate, including the phase correction and the chemical shift assignment. First, since the absolute phase is unknown, one of the difficulties the MR spectroscopist has to face is the determination of the correct phase correction. When only a few spectra have to be processed, this is usually performed manually. However, this correction needs to be automated as soon as a large number of spectra is involved, like in the case of phase coherent averaging or when the signals collected with phased array coils have to be combined. A second post-processing requirement is the frequency axis assignment. In standard mono-voxel MR spectroscopy, this can also be easily performed manually, by simply assigning a frequency value to a well-known resonance (e.g. the water or NAA resonance in the case of brain spectroscopy). However, when the correction of a frequency shift is required before averaging a large amount of spectra (due to B 0 spatial inhomogeneities in chemical shift imaging, or resulting from motion for example), this post-processing definitely needs to be performed automatically. Materials and methods Zero-order phase and frequency shift of a MR spectrum are linked respectively to zero-order and first-order phase variations in the corresponding free induction decay (FID) signal. One of the simplest ways to remove the phase component of a signal is to calculate the modulus of this signal: this approach is the basis of the correction technique presented here. Results We show that selecting the modulus of the FID allows, under certain conditions that are detailed, to automatically phase correct and frequency align the spectra. This correction technique can be for example applied to the summation of signals acquired from combined phased array coils, to phase coherent averaging and to B 0 shift correction. Conclusion We demonstrate that working on the modulus of the FID signal is a simple and efficient way to both phase correct and frequency align MR spectra automatically. This approach is particularly well suited to brain proton MR spectroscopy.
    Mots-clés : Biomedical Engineering, Computer Appl. in Life Sciences, crmbm, Free induction decay, Frequency assignment, Health Informatics, Imaging / Radiology, Modulus, MR spectroscopy, Phase correction, Post-processing, Solid State Physics.


Journal Article

  • Gineste, C, De Winter, JM, Kohl, C, Witt, CC, Giannesini, B, Brohm, K, Le Fur, Y, Gretz, N, Vilmen, C, Pecchi, E, Jubeau, M, Cozzone, PJ, Stienen, GJM, Granzier, H, Labeit, S, Ottenheijm, CAC, Bendahan, D & Gondin, J 2013, “In vivo and in vitro investigations of heterozygous nebulin knock-out mice disclose a mild skeletal muscle phenotype”, Neuromuscular disorders: NMD, vol. 23, no. 4, p. 357-369.
    Résumé : Nemaline myopathy is the most common congenital skeletal muscle disease, and mutations in the nebulin gene account for 50% of all cases. Recent studies suggest that the disease severity might be related to the nebulin expression levels. Considering that mutations in the nebulin gene are typically recessive, one would expect that a single functional nebulin allele would maintain nebulin protein expression which would result in preserved skeletal muscle function. We investigated skeletal muscle function of heterozygous nebulin knock-out (i.e., nebulin(+/-)) mice using a multidisciplinary approach including protein and gene expression analysis and combined in vivo and in vitro force measurements. Skeletal muscle anatomy and energy metabolism were studied strictly non-invasively using magnetic resonance imaging and 31P-magnetic resonance spectroscopy. Maximal force production was reduced by around 16% in isolated muscle of nebulin(+/-) mice while in vivo force generating capacity was preserved. Muscle weakness was associated with a shift toward a slower proteomic phenotype, but was not related to nebulin protein deficiency or to an impaired energy metabolism. Further studies would be warranted in order to determine the mechanisms leading to a mild skeletal muscle phenotype resulting from the expression of a single nebulin allele.
    Mots-clés : Animals, crmbm, Disease Models, Animal, Gene Expression, Heterozygote, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Male, Mice, Mice, Knockout, Muscle Proteins, Muscle Strength, Muscle Weakness, Muscle, Skeletal, Mutation, Myopathies, Nemaline, Phenotype, Severity of Illness Index.
    Note Note
    The following values have no corresponding Zotero field:<br />Author Address: Aix-Marseille Universite, CRMBM, 13005 Marseille, France; CNRS, Centre de Resonance Magnetique Biologique et Medicale (CRMBM), 13005 Marseille, France.<br />C2 - Muscle <br />ET - 2013/02/05<br />
    Note Note
    <p>Gineste, C<br/>De Winter, J M<br/>Kohl, C<br/>Witt, C C<br/>Giannesini, B<br/>Brohm, K<br/>Le Fur, Y<br/>Gretz, N<br/>Vilmen, C<br/>Pecchi, E<br/>Jubeau, M<br/>Cozzone, P J<br/>Stienen, G J M<br/>Granzier, H<br/>Labeit, S<br/>Ottenheijm, C A C<br/>Bendahan, D<br/>Gondin, J<br/>England<br/>Neuromuscular disorders : NMD<br/>Neuromuscul Disord. 2013 Apr;23(4):357-69. doi: 10.1016/j.nmd.2012.12.011. Epub 2013 Feb 1.</p>

  • Gineste, C, Duhamel, G, Le Fur, Y, Vilmen, C, Cozzone, PJ, Nowak, KJ, Bendahan, D & Gondin, J 2013, “Multimodal MRI and (31)P-MRS Investigations of the ACTA1(Asp286Gly) Mouse Model of Nemaline Myopathy Provide Evidence of Impaired In Vivo Muscle Function, Altered Muscle Structure and Disturbed Energy Metabolism”, PloS one, vol. 8, no. 8, p. e72294.
    Résumé : Nemaline myopathy (NM), the most common non-dystrophic congenital disease of skeletal muscle, can be caused by mutations in the skeletal muscle α-actin gene (ACTA1) (~25% of all NM cases and up to 50% of severe forms of NM). Muscle function of the recently generated transgenic mouse model carrying the human Asp286Gly mutation in the ACTA1 gene (Tg(ACTA1)(Asp286Gly)) has been mainly investigated in vitro. Therefore, we aimed at providing a comprehensive picture of the in vivo hindlimb muscle function of Tg(ACTA1)(Asp286Gly) mice by combining strictly noninvasive investigations. Skeletal muscle anatomy (hindlimb muscles, intramuscular fat volumes) and microstructure were studied using multimodal magnetic resonance imaging (Dixon, T2, Diffusion Tensor Imaging [DTI]). Energy metabolism was studied using 31-phosphorus Magnetic Resonance Spectroscopy ((31)P-MRS). Skeletal muscle contractile performance was investigated while applying a force-frequency protocol (1-150 Hz) and a fatigue protocol (6 min-1.7 Hz). Tg(ACTA1)(Asp286Gly) mice showed a mild muscle weakness as illustrated by the reduction of both absolute (30%) and specific (15%) maximal force production. Dixon MRI did not show discernable fatty infiltration in Tg(ACTA1)(Asp286Gly) mice indicating that this mouse model does not reproduce human MRI findings. Increased T2 values were observed in Tg(ACTA1)(Asp286Gly) mice and might reflect the occurrence of muscle degeneration/regeneration process. Interestingly, T2 values were linearly related to muscle weakness. DTI experiments indicated lower λ2 and λ3 values in Tg(ACTA1)(Asp286Gly) mice, which might be associated to muscle atrophy and/or the presence of histological anomalies. Finally (31)P-MRS investigations illustrated an increased anaerobic energy cost of contraction in Tg(ACTA1)(Asp286Gly) mice, which might be ascribed to contractile and non-contractile processes. Overall, we provide a unique set of information about the anatomic, metabolic and functional consequences of the Asp286Gly mutation that might be considered as relevant biomarkers for monitoring the severity and/or the progression of NM and for assessing the efficacy of potential therapeutic interventions.
    Mots-clés : crmbm.

  • Gineste, C, Le Fur, Y, Vilmen, C, Le Troter, A, Pecchi, E, Cozzone, PJ, Hardeman, EC, Bendahan, D & Gondin, J 2013, “Combined MRI and (31)P-MRS Investigations of the ACTA1(H40Y) Mouse Model of Nemaline Myopathy Show Impaired Muscle Function and Altered Energy Metabolism”, PloS one, vol. 8, no. 4, p. e61517.
    Résumé : Nemaline myopathy (NM) is the most common disease entity among non-dystrophic skeletal muscle congenital diseases. Mutations in the skeletal muscle α-actin gene (ACTA1) account for ∼25% of all NM cases and are the most frequent cause of severe forms of NM. So far, the mechanisms underlying muscle weakness in NM patients remain unclear. Additionally, recent Magnetic Resonance Imaging (MRI) studies reported a progressive fatty infiltration of skeletal muscle with a specific muscle involvement in patients with ACTA1 mutations. We investigated strictly noninvasively the gastrocnemius muscle function of a mouse model carrying a mutation in the ACTA1 gene (H40Y). Skeletal muscle anatomy (hindlimb muscles and fat volumes) and energy metabolism were studied using MRI and (31)Phosphorus magnetic resonance spectroscopy. Skeletal muscle contractile performance was investigated while applying a force-frequency protocol (from 1-150 Hz) and a fatigue protocol (80 stimuli at 40 Hz). H40Y mice showed a reduction of both absolute (-40%) and specific (-25%) maximal force production as compared to controls. Interestingly, muscle weakness was associated with an improved resistance to fatigue (+40%) and an increased energy cost. On the contrary, the force frequency relationship was not modified in H40Y mice and the extent of fatty infiltration was minor and not different from the WT group. We concluded that the H40Y mouse model does not reproduce human MRI findings but shows a severe muscle weakness which might be related to an alteration of intrinsic muscular properties. The increased energy cost in H40Y mice might be related to either an impaired mitochondrial function or an alteration at the cross-bridges level. Overall, we provided a unique set of anatomic, metabolic and functional biomarkers that might be relevant for monitoring the progression of NM disease but also for assessing the efficacy of potential therapeutic interventions at a preclinical level.
    Mots-clés : Actins, Animals, crmbm, Energy Metabolism, Female, Magnetic Resonance Imaging, Mice, Mice, Mutant Strains, Muscle, Skeletal, Myopathies, Nemaline.

  • Layec, G, Haseler, LJ, Hoff, J, Hart, CR, Liu, X, Le Fur, Y, Jeong, E-K & Richardson, RS 2013, “Short-term training alters the control of mitochondrial respiration rate before maximal oxidative ATP synthesis”, Acta Physiologica, vol. 208, no. 4, p. 376-386, viewed 29October,2014, .
    Résumé : Aim Short-term exercise training may induce metabolic and performance adaptations before any changes in mitochondrial enzyme potential. However, there has not been a study that has directly assessed changes in mitochondrial oxidative capacity or metabolic control as a consequence of such training in vivo. Therefore, we used 31P-magnetic resonance spectroscopy (31P-MRS) to examine the effect of short-term plantar flexion exercise training on phosphocreatine (PCr) recovery kinetics and the control of respiration rate. Method To this aim, we investigated 12 healthy men, experienced with this exercise modality (TRA), and 7 time-control subjects (TC). Results After 5 days of training, maximum work rate during incremental plantar flexion exercise was significantly improved (P < 0.01). During the recovery period, the maximal rate of oxidative adenosine triphosphate synthesis (PRE: 28 ± 13 mm min−1; POST: 26 ± 15 mm min−1) and the PCr recovery time constant (PRE: 31 ± 19 s; POST: 29 ± 16) were not significantly altered. In contrast, the Hill coefficient (nH) describing the co-operativity between respiration rate and ADP was significantly increased in TRA (PRE: nH = 2.7 ± 1.4; POST: nH = 3.4 ± 1.9, P < 0.05). Meanwhile, there were no systematic variations in any of these variables in TC. Conclusion This study reveals that 5 days of training induces rapid adaptation in the allosteric control of respiration rate by ADP before any substantial improvement in muscle oxidative capacity occurs.
    Mots-clés : 31P-MRS, exercise training, metabolic control, mitochondrial function, skeletal muscle energetics.
    Attachment Full Text PDF 509.9 kb (source)

  • Layec, G, Haseler, LJ, Trinity, JD, Hart, CR, Liu, X, Le Fur, Y, Jeong, E-K & Richardson, RS 2013, “Mitochondrial function and increased convective O2 transport: implications for the assessment of mitochondrial respiration in vivo”, Journal of Applied Physiology (Bethesda, Md.: 1985), vol. 115, no. 6, p. 803-811.
    Résumé : Although phosphorus magnetic resonance spectroscopy (31P-MRS)-based evidence suggests that in vivo peak mitochondrial respiration rate in young untrained adults is limited by the intrinsic mitochondrial capacity of ATP synthesis, it remains unknown whether a large, locally targeted increase in convective O2 delivery would alter this interpretation. Consequently, we examined the effect of superimposing reactive hyperemia (RH), induced by a period of brief ischemia during the last minute of exercise, on oxygen delivery and mitochondrial function in the calf muscle of nine young adults compared with free-flow conditions (FF). To this aim, we used an integrative experimental approach combining 31P-MRS, Doppler ultrasound imaging, and near-infrared spectroscopy. Limb blood flow [area under the curve (AUC), 1.4 ± 0.8 liters in FF and 2.5 ± 0.3 liters in RH, P < 0.01] and convective O2 delivery (AUC, 0.30 ± 0.16 liters in FF and 0.54 ± 0.05 liters in RH, P < 0.01), were significantly increased in RH compared with FF. RH was also associated with significantly higher capillary blood flow (P < 0.05) and faster tissue reoxygenation mean response times (70 ± 15 s in FF and 24 ± 15 s in RH, P < 0.05). This resulted in a 43% increase in estimated peak mitochondrial ATP synthesis rate (29 ± 13 mM/min in FF and 41 ± 14 mM/min in RH, P < 0.05) whereas the phosphocreatine (PCr) recovery time constant in RH was not significantly different (P = 0.22). This comprehensive assessment of local skeletal muscle O2 availability and utilization in untrained subjects reveals that mitochondrial function, assessed in vivo by 31P-MRS, is limited by convective O2 delivery rather than an intrinsic mitochondrial limitation.
    Mots-clés : Adult, Blood Flow Velocity, Energy Metabolism, Exercise, Hemoglobins, Humans, Hyperemia, Leg, Magnetic Resonance Spectroscopy, Male, Mitochondria, Muscle, Muscle, Skeletal, Oxygen Consumption, Phosphocreatine, Spectroscopy, Near-Infrared, Young Adult.

  • Layec, G, Malucelli, E, Le Fur, Y, Manners, D, Yashiro, K, Testa, C, Cozzone, PJ, Iotti, S & Bendahan, D 2013, “Effects of exercise-induced intracellular acidosis on the phosphocreatine recovery kinetics: a 31P MRS study in three muscle groups in humans”, NMR in Biomedicine, vol. 26, no. 11, p. 1403-1411, viewed 29October,2014, .
    Résumé : Little is known about the metabolic differences that exist among different muscle groups within the same subjects. Therefore, we used 31P-magnetic resonance spectroscopy (31P-MRS) to investigate muscle oxidative capacity and the potential effects of pH on PCr recovery kinetics between muscles of different phenotypes (quadriceps (Q), finger (FF) and plantar flexors (PF)) in the same cohort of 16 untrained adults. The estimated muscle oxidative capacity was lower in Q (29 ± 12 mM min-1, CVinter-subject = 42%) as compared with PF (46 ± 20 mM min-1, CVinter-subject = 44%) and tended to be higher in FF (43 ± 35 mM min-1, CVinter-subject = 80%). The coefficient of variation (CV) of oxidative capacity between muscles within the group was 59 ± 24%. PCr recovery time constant was correlated with end-exercise pH in Q (p < 0.01), FF (p < 0.05) and PF (p <0.05) as well as proton efflux rate in FF (p < 0.01), PF (p < 0.01) and Q (p = 0.12). We also observed a steeper slope of the relationship between end-exercise acidosis and PCr recovery kinetics in FF compared with either PF or Q muscles. Overall, this study supports the concept of skeletal muscle heterogeneity by revealing a comparable inter- and intra-individual variability in oxidative capacity across three skeletal muscles in untrained individuals. These findings also indicate that the sensitivity of mitochondrial respiration to the inhibition associated with cytosolic acidosis is greater in the finger flexor muscles compared with locomotor muscles, which might be related to differences in permeability in the mitochondrial membrane and, to some extent, to proton efflux rates. Copyright © 2013 John Wiley & Sons, Ltd.
    Mots-clés : crmbm, Exercise, Magnetic Resonance Spectroscopy, mitochondrial function, muscle acidosis, muscle oxidative capacity, skeletal muscle.
    Attachment Full Text PDF 264.9 kb (source)

  • Lutz, NW, Fur, YL, Chiche, J, Pouysségur, J & Cozzone, PJ 2013, “Quantitative In Vivo Characterization of Intracellular and Extracellular pH Profiles in Heterogeneous Tumors: A Novel Method Enabling Multiparametric pH Analysis”, Cancer Research, vol. 73, no. 15, p. 4616-4628, viewed 6January,2015, .
    Résumé : Acid production and transport are currently being studied to identify new targets for efficient cancer treatment, as subpopulations of tumor cells frequently escape conventional therapy owing to their particularly acidic tumor microenvironment. Heterogeneity in intracellular and extracellular tumor pH (pHi, pHe) has been reported, but none of the methods currently available for measuring tissue pH provides quantitative parameters characterizing pH distribution profiles in tissues. To this intent, we present here a multiparametric, noninvasive approach based on in vivo 31P nuclear magnetic resonance (NMR) spectroscopy and its application to mouse tumor xenografts. First, localized 31P NMR spectrum signals of pHi and pHe reporter molecules [inorganic phosphate (Pi) and 3-aminopropylphosphonate (3-APP), respectively] were transformed into pH curves using established algorithms. Although Pi is an endogenous compound, 3-APP had to be injected intraperitoneally. Then, we developed algorithms for the calculation of six to eight quantitative pH parameters from the digital points of each pH curve obtained. For this purpose, each pH distribution profile was approximated as a histogram, and intensities were corrected for the nonlinearity between chemical-shift and pH. Cancer Res; 73(15); 4616–28. ©2013 AACR
    Mots-clés : Animals, Cricetinae, crmbm, Hydrogen-Ion Concentration, Magnetic Resonance Spectroscopy, Mice, Neoplasms, Experimental, Xenograft Model Antitumor Assays.
    Attachment Full Text PDF 2.1 Mb (source)
    Attachment Full Text PDF 2.1 Mb (source)
  • Zink, J, Souteyrand, P, Guis, S, Chagnaud, C, Le Fur, Y, Militianu, D, Mattei, JP, Rozenbaum, M, Rosner, I, Boudinet, H, Bernard, M & Bendahan, D 2013, “Semi-Automatic Quantitative Investigation of Wrist Cartilage in Humans Using 3t Mri”, Annals of the Rheumatic Diseases, vol. 72, p. 1018-1019.


Journal Article

  • Chiche, J, Le Fur, Y, Vilmen, C, Frassineti, F, Daniel, L, Halestrap, AP, Cozzone, PJ, Pouysségur, J & Lutz, NW 2012, “In vivo pH in metabolic-defective Ras-transformed fibroblast tumors: key role of the monocarboxylate transporter, MCT4, for inducing an alkaline intracellular pH”, International journal of cancer. Journal international du cancer, vol. 130, no. 7, p. 1511-1520.
    Résumé : We present an investigation of tumor pH regulation, designed to support a new anticancer therapy concept that we had previously proposed. Our study uses a tumor model of ras-transformed hamster fibroblasts, CCL39, xenografted in the thighs of nude mice. We demonstrate, for the first time, that genetic modifications of specific mechanisms of proton production and/or proton transport result in distinct, reproducible changes in intracellular and extracellular tumor pH that can be detected and quantified noninvasively in vivo, simultaneously with determinations of tumor energetic status and necrosis in the same experiment. The CCL39 variants used were deficient in the sodium/proton exchanger, NHE-1, and/or in the monocarboxylate transporter, MCT4; further, variants were deficient in glycolysis or respiration. MCT4 expression markedly increased the gradient between intracellular and extracellular pH from 0.14 to 0.43 when compared to CCL39 wild-type tumors not expressing MCT4. The other genetic modifications studied produced smaller but significant increases in intracellular and decreases in extracellular pH. In general, increased pH gradients were paralleled by increased tumor growth performance and diminished necrotic regions, and 50% of the CCL39 variant expressing neither MCT4 nor NHE-1, but possessing full genetic capacity for glycolysis and oxidative phosphorylation, underwent regression before reaching a 1-cm diameter. Except for CCL39 wild-type tumors, no significant HIF-1α expression was detected. Our in vivo results support a multipronged approach to tumor treatment based on minimizing intracellular pH by targeting several proton production and proton transport processes, among which the very efficient MCT4 proton/lactate co-transport deserves particular attention.
    Mots-clés : Animals, Cell Line, Tumor, Cell Transformation, Neoplastic, Cricetinae, crmbm, Fibroblasts, Genes, ras, Glycolysis, Hydrogen-Ion Concentration, Hypoxia-Inducible Factor 1, alpha Subunit, Ion Exchange, Ion Transport, Mice, Mice, Nude, Monocarboxylic Acid Transporters, Muscle Proteins, Mutation, Necrosis, Oxidative Phosphorylation, Phospholipids, Protons, Sodium-Hydrogen Antiporter.

  • Laigle, C, Confort-Gouny, S, Le Fur, Y, Cozzone, PJ & Viola, A 2012, “Deletion of TRAAK potassium channel affects brain metabolism and protects against ischemia”, PloS one, vol. 7, no. 12, p. e53266.
    Résumé : Cerebral stroke is a worldwide leading cause of disability. The two-pore domain K⁺ channels identified as background channels are involved in many functions in brain under physiological and pathological conditions. We addressed the hypothesis that TRAAK, a mechano-gated and lipid-sensitive two-pore domain K⁺ channel, is involved in the pathophysiology of brain ischemia. We studied the effects of TRAAK deletion on brain morphology and metabolism under physiological conditions, and during temporary focal cerebral ischemia in Traak⁻/⁻ mice using a combination of in vivo magnetic resonance imaging (MRI) techniques and multinuclear magnetic resonance spectroscopy (MRS) methods. We provide the first in vivo evidence establishing a link between TRAAK and neurometabolism. Under physiological conditions, Traak⁻/⁻ mice showed a particular metabolic phenotype characterized by higher levels of taurine and myo-inositol than Traak⁺/⁺ mice. Upon ischemia, Traak⁻/⁻ mice had a smaller infarcted volume, with lower contribution of cellular edema than Traak⁺/⁺ mice. Moreover, brain microcirculation was less damaged, and brain metabolism and pH were preserved. Our results show that expression of TRAAK strongly influences tissue levels of organic osmolytes. Traak⁻/⁻ mice resilience to cellular edema under ischemia appears related to their physiologically high levels of myo-inositol and of taurine, an aminoacid involved in the modulation of mitochondrial activity and cell death. The beneficial effects of TRAAK deletion designate this channel as a promising pharmacological target for the treatment against stroke.
    Mots-clés : Animals, Brain, crmbm, Cytoprotection, Energy Metabolism, Female, Gene Deletion, Hypoxia-Ischemia, Brain, Infarction, Middle Cerebral Artery, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Potassium Channels.

  • Layec, G, Bringard, A, Yashiro, K, Le Fur, Y, Vilmen, C, Micallef, J-P, Perrey, S, Cozzone, PJ & Bendahan, D 2012, “The slow components of phosphocreatine and pulmonary oxygen uptake can be dissociated during heavy exercise according to training status”, Experimental physiology, vol. 97, no. 8, p. 955-969.
    Résumé : To better understand the mechanisms underlying the pulmonary O(2) uptake (V(O(2P))) slow component during high-intensity exercise, we used (31)P magnetic resonance spectroscopy, gas exchange, surface electromyography and near-infrared spectroscopy measurements to examine the potential relationship between the slow components of V(O(2P)) and phosphocreatine (PCr), muscle recruitment and tissue oxygenation in endurance-trained athletes and sedentary subjects. Specifically, six endurance-trained and seven sedentary subjects performed a dynamic high-intensity exercise protocol during 6 min at an exercise intensity corresponding to 35-40% of knee-extensor maximal voluntary contraction. The slow component of V(O(2P))(117 ± 60 ml min(-1), i.e. 20 ± 10% of the total response) was associated with a paradoxical PCr resynthesis in endurance-trained athletes (-0.90 ± 1.27 mm, i.e. -12 ± 16% of the total response). Meanwhile, oxygenated haemoglobin increased throughout the second part of exercise and was significantly higher at the end of exercise compared with the value at 120 s (P < 0.05), whereas the integrated EMG was not significantly changed throughout exercise. In sedentary subjects, a slow component was simultaneously observed for V(O(2P)) and [PCr] time-dependent changes (208 ± 14 ml min(-1), i.e. 38 ± 18% of the total V(O(2P))response, and 1.82 ± 1.39 mm, i.e. 16 ± 13% of the total [PCr] response), but the corresponding absolute or relative amplitudes were not correlated. The integrated EMG was significantly increased throughout exercise in sedentary subjects. Taken together, our results challenge the hypothesis of a mechanistic link between [PCr] and V(O(2P)) slow components and demonstrate that, as a result of a tighter metabolic control and increased O(2) availability, the [PCr] slow component can be minimized in endurance-trained athletes while the V(O(2P)) slow component occurs.
    Mots-clés : Adult, crmbm, Electromyography, Exercise, Female, Humans, Knee, Magnetic Resonance Spectroscopy, Male, Muscle Contraction, Muscle, Skeletal, Oxygen Consumption, Phosphocreatine, Physical Endurance, Pulmonary Gas Exchange, Sedentary Lifestyle, Young Adult.

  • Simões, RV, Ortega-Martorell, S, Delgado-Goñi, T, Le Fur, Y, Pumarola, M, Candiota, AP, Martín, J, Stoyanova, R, Cozzone, PJ, Julià-Sapé, M & Arús, C 2012, “Improving the classification of brain tumors in mice with perturbation enhanced (PE)-MRSI”, Integrative biology: quantitative biosciences from nano to macro, vol. 4, no. 2, p. 183-191.
    Résumé : Classifiers based on statistical pattern recognition analysis of MRSI data are becoming important tools for the non-invasive diagnosis of human brain tumors. Here we investigate the potential interest of perturbation-enhanced MRSI (PE-MRSI), in this case acute hyperglycemia, for improving the discrimination between mouse brain MRS patterns of glioblastoma multiforme (GBM), oligodendroglioma (ODG), and non-tumor brain parenchyma (NT). Six GBM-bearing mice and three ODG-bearing mice were scanned at 7 Tesla by PRESS-MRSI with 12 and 136 ms echo-time, during euglycemia (Eug) and also during induced acute hyperglycemia (Hyp), generating altogether four datasets per animal (echo time + glycemic condition): 12Eug, 136Eug, 12Hyp, and 136Hyp. For classifier development all spectral vectors (spv) selected from the MRSI matrix were unit length normalized (UL2) and used either as a training set (76 GBM spv, four mice; 70 ODG spv, two mice; 54 NT spv) or as an independent testing set (61 GBM spv, two mice; 31 ODG, one mouse; 23 NT spv). All Fisher's LDA classifiers obtained were evaluated as far as their descriptive performance-correctly classified cases of the training set (bootstrapping)-and predictive accuracy-balanced error rate of independent testing set classification. MRSI-based classifiers at 12Hyp were consistently more efficient in separating GBM, ODG, and NT regions, with overall accuracies always >80% and up to 95-96%; remaining classifiers were within the 48-85% range. This was also confirmed by user-independent selection of training and testing sets, using leave-one-out (LOO). This highlights the potential interest of perturbation-enhanced MRSI protocols for improving the non-invasive characterization of preclinical brain tumors.
    Mots-clés : Animals, Blood Glucose, Brain Neoplasms, Female, Glioblastoma, Histocytochemistry, Hyperglycemia, Magnetic Resonance Spectroscopy, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Oligodendroglioma, Pattern Recognition, Automated.


Journal Article

  • Giannesini, B, Le Fur, Y, Cozzone, PJ, Verleye, M, Le Guern, M-E & Bendahan, D 2011, “Citrulline malate supplementation increases muscle efficiency in rat skeletal muscle”, European journal of pharmacology, vol. 667, no. 1-3, p. 100-104.
    Résumé : Citrulline malate (CM; CAS 54940-97-5, Stimol®) is known to limit the deleterious effect of asthenic state on muscle function, but its effect under healthy condition remains poorly documented. The aim of this longitudinal double-blind study was to investigate the effect of oral ingestion of CM on muscle mechanical performance and bioenergetics in normal rat. Gastrocnemius muscle function was investigated strictly non-invasively using nuclear magnetic resonance techniques. A standardized rest-stimulation- (5.7 min of repeated isometric contractions electrically induced by transcutaneous stimulation at a frequency of 3.3 Hz) recovery-protocol was performed twice, i.e., before (t(0)-24 h) and after (t(0)+48 h) CM (3 g/kg/day) or vehicle treatment. CM supplementation did not affect PCr/ATP ratio, [PCr], [Pi], [ATP] and intracellular pH at rest. During the stimulation period, it lead to a 23% enhancement of specific force production that was associated to significant decrease in both PCr (28%) and oxidative (32%) costs of contraction, but had no effect on the time-courses of phosphorylated compounds and intracellular pH. Furthermore, both the rate of PCr resynthesis during the post-stimulation period (VPCr(rec)) and the oxidative ATP synthesis capacity (Q(max)) remained unaffected by CM treatment. These data demonstrate that CM supplementation under healthy condition has an ergogenic effect associated to an improvement of muscular contraction efficiency.
    Mots-clés : Administration, Oral, Animals, Biomechanics, Citrulline, crmbm, Electric Stimulation, Energy Metabolism, Malates, Male, Muscle, Skeletal, Oxidation-Reduction, Rats, Rats, Wistar.

  • Gondin, J, Giannesini, B, Vilmen, C, Le Fur, Y, Cozzone, PJ & Bendahan, D 2011, “Effects of a single bout of isometric neuromuscular electrical stimulation on rat gastrocnemius muscle: a combined functional, biochemical and MRI investigation”, Journal of electromyography and kinesiology: official journal of the International Society of Electrophysiological Kinesiology, vol. 21, no. 3, p. 525-532.
    Résumé : While muscle damage resulting from electrically-induced muscle isometric contractions has been reported in humans, animal studies have failed to illustrate similar deleterious effects and it remains to be determined whether these conflicting results are related to differences regarding experimental procedures or to species. We have investigated in vivo, in rat gastrocnemius muscles, using experimental conditions as close as possible to those used in humans (i.e., muscle length, number of contractions, stimulated muscle), the effects of a single bout of neuromuscular electrical stimulation (NMES). Maximal tetanic force was measured before, immediately after and 1h and 1, 2, 3, 7 and 14 days after NMES. Magnetic resonance imaging measurements, including volume of gastrocnemius muscles and proton transverse relaxation time (T(2)) were performed at baseline and 3, 7, and 14 days after the NMES session. Control animals did not perform any exercise and measurements were recorded at the same time points. For both groups, blood creatine kinase (CK) activity was measured within the first 3 days that followed the initial evaluation. Maximal tetanic force decreased immediately after NMES whereas measurements performed 1h and the days afterwards were similar to the baseline values. CK activity, muscle volume and T(2) values were similar throughout the experimental protocol between the two groups. Under carefully controlled experimental conditions, isometric NMES per se did not induce muscle damage in rat gastrocnemius muscles on the contrary to what has been repeatedly reported in humans. Further experiments would then be warranted in order to clearly delineate these differences and to better understand the physiological events associated with muscle damage resulting from NMES-induced isometric contractions.
    Mots-clés : Animals, crmbm, Electric Stimulation, Isometric Contraction, Magnetic Resonance Imaging, Male, Muscle Fatigue, Muscle, Skeletal, Physical Endurance, Rats, Rats, Wistar.

  • Herzog, W, Sartorio, A, Lafortuna, CL, Kanehisa, H, Fukunaga, T, Dotan, R, Falk, B, Wood, LE, Tonson, A, Le Fur, Y, Cozzone, PJ, Bendahan, D, Tolfrey, K, Morse, CI, O'Brien, TD, Reeves, ND, Baltzopoulos, V, Jones, DA, Maganaris, CN, Lambertz, D, Grosset, J-F & Perot, C 2011, “Commentaries on Viewpoint: can muscle size fully account for strength differences between children and adults?”, Journal of applied physiology (Bethesda, Md.: 1985), vol. 110, no. 6, p. 1750-1753; discussion on page 1754.

  • Layec, G, Bringard, A, Le Fur, Y, Vilmen, C, Micallef, J-P, Perrey, S, Cozzone, PJ & Bendahan, D 2011, “Comparative determination of energy production rates and mitochondrial function using different 31P MRS quantitative methods in sedentary and trained subjects”, NMR in biomedicine, vol. 24, no. 4, p. 425-438.
    Résumé : Muscle energetics has been largely and quantitatively investigated using (31)P MRS. Various methods have been used to estimate the corresponding rate of oxidative ATP synthesis (ATP(ox)); however, potential differences among methods have not been investigated. In this study, we aimed to compare the rates of ATP production and energy cost in two groups of subjects with different training status using four different methods: indirect method (method 1), ADP control model (method 2) and phosphate potential control model (method 3). Method 4 was a modified version of method 3 with the introduction of a correction factor allowing for similar values to be obtained for the end-exercise oxidative ATP synthesis rate inferred from exercise measurements and the initial recovery phosphocreatine resynthesis rate. Seven sedentary and seven endurance-trained subjects performed a dynamic standardised rest-exercise-recovery protocol. We quantified the rates of ATP(ox) and anaerobic ATP synthesis (ATP(ana)) using (31)P MRS data recorded at 1.5 T. The rates of ATP(ox) over the entire exercise session were independent of the method used, except for method 4 which provided significantly higher values in both groups (p < 0.01). In addition, methods 1-3 were cross-correlated, thereby confirming their statistical agreement. The rate of ATP(ana) was significantly higher with method 1 (p < 0.01) and lower with method 4 (p < 0.01). As a result of the higher rate of ATP(ox), EC (method 4) calculated over the entire exercise session was higher and initial EC (method 1) was lower in both groups compared with the other methods. We showed in this study that the rate of ATP(ox) was independent of the calculation method, as long as no corrections (method 4) were performed. In contrast, results related to the rates of ATP(ana) were strongly affected by the calculation method and, more exactly, by the estimation of protons generated by ATP(ox). Although the absolute EC values differed between the methods, within- or between-subject comparisons are still valid given the tight relationships between them.
    Mots-clés : Adenosine Diphosphate, Adenosine Triphosphate, Adult, Anaerobiosis, crmbm, Energy Metabolism, Exercise, Female, Humans, Hydrogen-Ion Concentration, Knee, Magnetic Resonance Spectroscopy, Male, Mitochondria, Muscle, Muscles, Oxidation-Reduction, Phosphorus Isotopes, Phosphorylation, Sedentary Lifestyle.

  • Viola, A, Confort-Gouny, S, Schneider, JF, Le Fur, Y, Viout, P, Chapon, F, Pineau, S, Cozzone, PJ & Girard, N 2011, “Is brain maturation comparable in fetuses and premature neonates at term equivalent age?”, AJNR. American journal of neuroradiology, vol. 32, no. 8, p. 1451-1458.
    Résumé : BACKGROUND AND PURPOSE: Improved knowledge of brain maturation in fetuses and premature neonates is crucial for the early detection of pathologies and would help determine whether MR data from the premature brain might be used to evaluate fetal maturation. Using diffusion-weighted MR imaging and (1)H-MR spectroscopy, we compared cerebral microstructure and metabolism in normal in utero fetuses imaged near term and premature neonates imaged at term equivalent. MATERIALS AND METHODS: Forty-eight subjects were investigated: 24 in utero fetuses (mean gestational age, 37 ± 1 weeks) and 24 premature neonates (mean postconceptional age, 37 ± 1 weeks). ADC values were measured in cerebellum, pons, white matter, brain stem, basal ganglia, and thalamus. MR spectroscopy was performed in deep white matter. RESULTS: Mean ADC values from fetuses and premature neonates were comparable except for the pons and the parietal white matter. ADC values were lower in the pons of premature neonates, whereas greater values were found in their parietal white matter compared with fetuses. Proton MR spectroscopy showed higher levels of NAA/H(2)O, Glx/H(2)O, tCr/H(2)O, and mIns/H(2)O in premature neonates compared with fetuses. CONCLUSIONS: Our study provides evidence of subtle anomalies in the parietal white matter of healthy premature neonates. In addition, the reduced ADC values in the pons together with the increased levels of NAA/H(2)O, tCr/H(2)O, and Glx/H(2)O in the centrum semiovale suggest a more advanced maturation in some white matter regions. Our results indicate that MR data from the premature brain are not appropriate for the assessment of the fetal brain maturation.
    Mots-clés : Brain, crmbm, Fetal Organ Maturity, Fetus, Gestational Age, Humans, Infant, Newborn, Infant, Premature, Term Birth.

  • Zaaraoui, W, Reuter, F, Rico, A, Faivre, A, Crespy, L, Malikova, I, Soulier, E, Viout, P, Le Fur, Y, Confort-Gouny, S, Cozzone, PJ, Pelletier, J, Ranjeva, J-P & Audoin, B 2011, “Occurrence of neuronal dysfunction during the first 5 years of multiple sclerosis is associated with cognitive deterioration”, Journal of neurology, vol. 258, no. 5, p. 811-819.
    Résumé : Brain neuronal injury is present in patients suffering from multiple sclerosis (MS) from the earliest stage of the disease; however, the functional counterpart of early neuronal injury is largely unknown. The goal of this study was to assess the potential impact of early neuronal dysfunction affecting white matter (WM), grey matter (GM), or the cerebellum on cognitive deterioration and/or EDSS progression during the first 5 years of MS. Magnetic resonance spectroscopic (MRS) examinations and neuropsychological assessments were performed in 23 patients included after the first clinical attack of MS and 24 healthy controls. The same protocol was performed in patients after a follow-up of 5 years. Metabolic neuronal function was assessed in WM (splenium of corpus callosum), GM (dorsal posterior cingulate cortex), and the cerebellum by evaluating N-acetylaspartate (NAA) levels. During follow-up, 39% of patients showed cognitive deterioration and 43% showed a deterioration in their EDSS. Patients with cognitive deterioration had greater NAA level reductions during follow-up in the cerebellum (p = 0.003) and WM (p = 0.02) compared to patients without cognitive deterioration. In addition, patients with cognitive deterioration had higher progression of T2 lesion load (T2LL) during the follow-up period compared to patients without cognitive deterioration (p = 0.03). No differences between patients with and without EDSS progression in terms of NAA levels or T2LL were observed. The present longitudinal study found evidence that, during the first 5 years of MS, cognitive deterioration is associated with the progression of neuronal dysfunction and tissue injury as assessed by MRS and T2LL, respectively.
    Mots-clés : Adult, Aspartic Acid, Cognition Disorders, crmbm, Disease Progression, Female, Humans, Magnetic Resonance Spectroscopy, Male, Multiple sclerosis, Neurons, Neuropsychological Tests, Young Adult.


Journal Article

  • Callot, V, Duhamel, G, Le Fur, Y, Decherchi, P, Marqueste, T, Kober, F & Cozzone, PJ 2010, “Echo planar diffusion tensor imaging of the mouse spinal cord at thoracic and lumbar levels: A feasibility study”, Magnetic resonance in medicine, vol. 63, no. 4, p. 1125-1134.
    Résumé : Diffusion tensor imaging is increasingly used for probing spinal cord (SC) pathologies, especially in mouse models of human diseases. However, diffusion tensor imaging series requires a long acquisition time and mouse experiments rarely use rapid imaging techniques such as echo planar imaging. A recent preliminary study demonstrated the feasibility and robustness of the echo planar imaging sequence for mouse cervical SC diffusion tensor imaging investigations. The feasibility of echo planar imaging at thoracic and lumbar levels, however, remained unknown due to bulk motion, field inhomogeneities, and off-centering of the SC in the axial plane. In the present study, the feasibility and the robustness of an echo planar imaging-based diffusion tensor imaging sequence for mouse thoracic and lumbar SC investigations is demonstrated. Quantitative and accurate diffusion tensor imaging metrics, as well as high spatially resolved images, have been obtained. This successful demonstration may open new perspectives in the field of mouse SC imaging. Echo planar imaging is used in several imaging modalities, such as relaxometry or perfusion, and may prove to be very attractive for multimodal MR investigations to acquire a more detailed characterization of the SC tissue.
    Mots-clés : Analysis of Variance, Animals, crmbm, Diffusion Magnetic Resonance Imaging, Echo-Planar Imaging, Feasibility Studies, Image Processing, Computer-Assisted, Lumbar Vertebrae, Male, Mice, Sensitivity and Specificity, Spinal cord, Thoracic Vertebrae.

  • Didic, M, Ranjeva, J-P, Barbeau, E, Confort-Gouny, S, Fur, YL, Felician, O, Mancini, J, Poncet, M, Ceccaldi, M & Cozzone, P 2010, “Impaired visual recognition memory in amnestic mild cognitive impairment is associated with mesiotemporal metabolic changes on magnetic resonance spectroscopic imaging”, Journal of Alzheimer's disease: JAD, vol. 22, no. 4, p. 1269-1279.
    Résumé : In the early stages of Alzheimer's disease (AD), neurofibrillary tangles develop in the mesial temporal lobe (MTL), first in the anterior subhippocampal (perirhinal/entorhinal) cortex and then in the hippocampal formation. This region plays a key role in visualrecognition memory (VRM). VRM has been reported to be impaired in patients with amnestic mild cognitive impairment (aMCI). The aim of the present study was to determine if an impairment of VRM is associated with metabolic changes in the MTL using magnetic resonance spectroscopic imaging and if evaluating VRM can contribute to the early diagnosis of AD. 28 patients with aMCI and 28 controls underwent a full neuropsychological assessment including an evaluation of VRM using the DMS48. NAA/mIno ratios, reduced in patients with AD and associated with the severity of pathological changes, were determined in the MTL. aMCI-patients were further divided into two subgroups according to their VRM performance. aMCI-patients showed decreased NAA/mIno levels in the right hippocampus compared with controls. aMCI-patients with impaired VRM showed decreased NAA/mIno ratios in the MTL bilaterally, including a region that sampled the left anterior subhippocampal cortex, compared to controls. No changes were found in aMCI patients with normal VRM. Performance on the DMS48 correlated with NAA/mIno levels in the anterior MTL. Clinical 6-year follow-up data (available for 78.6% of the aMCI-patients) indicates that impaired performance on the DMS48 could predict conversion to AD with a sensitivity and specificity of 81.8%. These findings provide further evidence that impaired VRM, as a hallmark of MTL dysfunction, may contribute to the early diagnosis of AD.
    Mots-clés : Aged, Aged, 80 and over, Amnesia, Analysis of Variance, Brain Mapping, Cognition Disorders, crmbm, Female, hippocampus, Humans, Magnetic Resonance Spectroscopy, Male, Middle Aged, Neuropsychological Tests, Recognition (Psychology), Statistics, Nonparametric, Temporal Lobe.

  • Giannesini, B, Vilmen, C, Le Fur, Y, Dalmasso, C, Cozzone, PJ & Bendahan, D 2010, “A strictly noninvasive MR setup dedicated to longitudinal studies of mechanical performance, bioenergetics, anatomy, and muscle recruitment in contracting mouse skeletal muscle”, Magnetic resonance in medicine: official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine, vol. 64, no. 1, p. 262-270.
    Résumé : MR techniques have proven their ability to investigate skeletal muscle function in situ. Their benefit in terms of noninvasiveness is, however, lost in animal research, given that muscle stimulation and force output measurements are usually achieved using invasive surgical procedures, thereby excluding repeated investigations in the same animal. This study describes a new setup allowing strictly noninvasive investigations of mouse gastrocnemius muscle function using (1)H-MRI and (31)P-MR spectroscopy. Its originality is to integrate noninvasive systems for inducing muscle contraction through transcutaneous stimulation and for measuring mechanical performance with a dedicated ergometer. In order to test the setup, muscle function was investigated using a fatiguing stimulation protocol (6 min of repeated isometric contractions at 1.7 Hz). T(2)-weighted imaging demonstrated that transcutaneous stimulation mainly activated the gastrocnemius. Moreover, investigations repeated twice with a 7-day interval between bouts did show a high reproducibility in measurements with regard to changes in isometric force and energy metabolism. In conclusion, this setup enables us for the first time to access mechanical performance, energy metabolism, anatomy, and physiology strictly noninvasively in contracting mouse skeletal muscle. The possibility for implementing longitudinal studies opens up new perspectives in many research areas, including ageing, pharmaceutical research, and gene and cell therapy.
    Mots-clés : Animals, Energy Metabolism, Hindlimb, Longitudinal Studies, Magnetic Resonance Spectroscopy, Mice, Mice, Inbred C57BL, Muscle Contraction, Muscle, Skeletal, Reproducibility of Results.

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