Yann Le Fur

Aix-Marseille Université, Marsiglia, Provence-Alpes-Côte d'Azur, France

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Publications (149)360.57 Total impact

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    ABSTRACT: 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 remains 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: 31P magnetic resonance spectroscopy measurements were performed in thirteen young healthy males during a standardized rest-exercise-recovery protocol before (D0), two days (D2) and four days (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 due to the increased [Pi] (+43% and +32%, respectively) while 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 due 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 non-contractile processes and/or adaptive mechanisms to muscle damage might account for the decreased Ec during the dynamic exercise.
    Medicine &amp Science in Sports &amp Exercise 06/2015; · 4.48 Impact Factor
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    ABSTRACT: 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 a-tropomyosin slow gene (TPM3). Considering the conflicting findings of the previous studies on the transgenic (Tg) mice carrying the TPM3 Met9Arg 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.
    PloS one. 09/2014; 9(9).
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    ABSTRACT: This study compared the metabolic and activation changes induced by electrically-evoked (NMES) and voluntary (VOL) contractions performed at the same submaximal intensity using P chemical shift imaging (CSI) and T2 mapping investigations.
    Medicine and science in sports and exercise. 09/2014;
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    ABSTRACT: 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 ((31)P 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.
    The Journals of Gerontology Series A Biological Sciences and Medical Sciences 08/2014; · 4.31 Impact Factor
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    ABSTRACT: Although skeletal muscle work efficiency likely 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 1) maximal intermittent contractions to elicit a metabolic demand from both cross-bridge cycling and ion pumping and 2) 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 ± 0.22 mM.min-1.N m-1) compared to the young (0.13 ± 0.03 mM.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 ± 0.07 mM.min-1.N m-1) was not different from the young (0.06 ± 0.02 mM.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, likely 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.
    Clinical science (London, England : 1979). 08/2014;
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    ABSTRACT: 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.
    Magma (New York, N.Y.). 06/2014;
  • Yann Le Fur, Patrick J Cozzone
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    ABSTRACT: 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.
    Magma (New York, N.Y.). 06/2014;
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    ABSTRACT: Capsiate is known to increase whole body oxygen consumption possibly via the activation of uncoupling processes, but its effect at skeletal muscle level remains poorly documented and conflicting. To clarify this issue, gastrocnemius muscle function and energetics were investigated in mice, 2 hours after a single intake of either vehicle (control) or purified capsiate (at 10- or 100-mg/kg body weight), through a multidisciplinary approach combining in vivo and in vitro measurements. Mechanical performance and energy pathway fluxes were accessed 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 to control, both capsiate doses produced quantitatively similar effects at the energy metabolism level, including an about 2-fold decrease of the mitochondrial respiration sensitivity for ADP. Interestingly, they did alter neither oxidative phosphorylation nor 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 10-mg and 100-mg groups, respectively). ATP cost of contraction was further reduced in 10-mg (-35%) and 100-mg (-45%) groups. Besides, the highest dose also increased the 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.
    AJP Endocrinology and Metabolism 03/2014; · 4.51 Impact Factor
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    ABSTRACT: Impaired skeletal muscle efficiency potentially contributes to the age-related decline in exercise capacity and may explain the altered hemodynamic response to exercise in the elderly. Thus, we examined whether 1) the ATP cost of contraction increases with age, and 2) this results in altered convective O2 delivery to maintain microvascular oxygenation in the calf muscle. To this aim, we used an integrative experimental approach combining phosphorus magnetic resonance spectroscopy (31P-MRS), Doppler ultrasound imaging, and near-infrared spectroscopy (NIRS) during dynamic plantar flexion exercise at 40% of maximal power output (WRmax) 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-1.W-1) compared with the young (2.4 ± 1.9 mM.min-1.W-1, P<0.05) and this was only significantly correlated with plantar flexion WRmax in the old (r=-0.52, P<0.05). Even when differences in power output were taken into account, end-exercise blood flow (old: 259 ± 168; young: 134 ± 40 ml.min-1.W-1, P<0.05) and convective O2 delivery (old: 0.048 ± 0.031; young: 0.026 ± 0.008 L.min-1.W-1, P<0.05) were greater in the old in comparison to the young. In contrast, NIRS oxy-, deoxy-hemoglobin and microvascular oxygenation indices were not significantly different between groups (P>0.05). Therefore, this study reveals that, while the peripheral hemodynamic responses to plantar flexion exercise appear to be appropriate, the elevated energy cost of contraction and associated reduction in WRmax in this muscle group may play a role in limiting exercise capacity with age.
    Clinical Science 11/2013; · 4.86 Impact Factor
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    ABSTRACT: Although phosphorus magnetic resonance spectroscopy ((31)P-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 hyperaemia (RH), induced by a period of brief ischemia during the last min of exercise, on oxygen delivery and mitochondrial function in the calf muscle of 9 young adults in comparison to free-flow conditions (FF). To this aim, we used an integrative experimental approach combining (31)P-MRS, Doppler ultrasound imaging, and near-infrared spectroscopy. Limb blood flow [area under the curve (AUC), 1.4±0.8 L in FF and 2.5±0.3 L in RH, P<0.01] and convective O2 delivery (AUC, 0.30±0.16 L in FF and 0.54±0.05 L in RH, 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 faster tissue re-oxygenation 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(-1) in FF and 41±14 mM.min(-1) 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 (31)P-MRS, is limited by convective O2 delivery rather than an intrinsic mitochondrial limitation.
    Journal of Applied Physiology 06/2013; · 3.48 Impact Factor
  • Yann Le Fur, Patrick J Cozzone
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    ABSTRACT: 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. 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. 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. 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.
    MAGMA Magnetic Resonance Materials in Physics Biology and Medicine 06/2013; · 1.86 Impact Factor
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    ABSTRACT: 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 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. While 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. For each histogram derived from a Pi or 3-APP resonance, we obtained the following tumor pH profile parameters: weighted mean, weighted median, mode(s), skewness (asymmetry), kurtosis (peakedness), and entropy (smoothness). In addition, relative sizes of tissue volumes defined by characteristic pH ranges were estimated by integration and/or by fitting the curve to multiple modes. Our algorithms and the results obtained for animal models were validated (i) by computer simulations of 31P NMR resonances and pH profiles; and (ii) by comparison with combinations of ≤ 3 test solutions at well-defined pH values, containing the pH reporter molecule 3-APP. All calculations were performed with an EXCEL spreadsheet, thus avoiding any specialized software or hardware. Consequently, heterogeneous pHi and pHe distribution profiles in tumors can be characterized by multiple quantitative parameters derived from classical statistics, through pH distribution profiles obtained from in vivo 31P NMR spectra. This original technique is helpful in analyzing tumor tissue features with increased detail, by a single experiment also yielding information on underlying energy and phospholipid metabolism.
    Cancer Research 06/2013; · 9.28 Impact Factor
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    ABSTRACT: Little is known about the metabolic differences that exist among different muscle groups within the same subjects. Therefore, we used (31) P-magnetic resonance spectroscopy ((31) P-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.
    NMR in Biomedicine 05/2013; · 3.45 Impact Factor
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    ABSTRACT: Nemaline myopathy (NM) is the most common disease entity among non-dystrophic skeletal muscle congenital diseases. Mutations in the skeletal muscle a-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 (240%) and specific (225%) 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.
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    ABSTRACT: 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 (31) P-magnetic resonance spectroscopy ((31) P-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 ATP 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 cooperativity 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. This article is protected by copyright. All rights reserved.
    Acta Physiologica 04/2013; · 4.38 Impact Factor
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    ABSTRACT: 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 +/À) 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 +/À 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.
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    ABSTRACT: 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.
    Neuromuscular Disorders 01/2013; · 3.46 Impact Factor
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    ABSTRACT: 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.
    PLoS ONE 01/2013; 8(4):e61517. · 3.53 Impact Factor
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    ABSTRACT: 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.
    PLoS ONE 01/2013; 8(8):e72294. · 3.53 Impact Factor

Publication Stats

1k Citations
360.57 Total Impact Points

Institutions

  • 2002–2014
    • Aix-Marseille Université
      • • Centre de Résonance Magnétique Biologique et Médicale (UMR 7339 CRMBM)
      • • Faculté de Médecine
      Marsiglia, Provence-Alpes-Côte d'Azur, France
    • UCL Eastman Dental Institute
      Londinium, England, United Kingdom
  • 2013
    • University of Utah
      • Division of Geriatrics
      Salt Lake City, UT, United States
  • 1988–2011
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 2008–2010
    • Institut de Recherche sur les Phénomènes Hors Equilibre
      Marsiglia, Provence-Alpes-Côte d'Azur, France
    • Université Blaise Pascal - Clermont-Ferrand II
      • Laboratoire des Adaptations Métaboliques à l’Exercice en conditions Physiologiques et Pathologiques AME2P, EA 3533
      Clermont, Auvergne, France
  • 2007–2008
    • University Children's Hospital Basel
      Bâle, Basel-City, Switzerland
    • University of Nantes
      Naoned, Pays de la Loire, France
  • 2006
    • Institut National du Sport, de l'Expertise et de la Performance
      Lutetia Parisorum, Île-de-France, France
  • 2005–2006
    • Assistance Publique Hôpitaux de Marseille
      • Service de neurologie
      Marseille, Provence-Alpes-Cote d'Azur, France
  • 2001
    • University of Liverpool
      Liverpool, England, United Kingdom
  • 1992–1998
    • University Joseph Fourier - Grenoble 1
      Grenoble, Rhône-Alpes, France