Myostatin is a key mediator between energy metabolism and endurance capacity of skeletal muscle

Myostatin (Mstn) participates in the regulation of skeletal muscle size and has emerged as a regulator of muscle metabolism. Here, we hypothesized that lack of myostatin profoundly depresses oxidative phosphorylation-dependent muscle function. Toward this end, we explored Mstn/ mice as a model for the constitutive absence of myostatin and AAV-mediated overexpression of myostatin propeptide as a model of myostatin blockade in adult wild-type mice. We show that muscles from Mstn/ mice, although larger and stronger, fatigue extremely rapidly. Myostatin deficiency shifts muscle from aerobic toward anaerobic energy metabolism, as evidenced by decreased mitochondrial respiration, reduced expression of PPAR transcriptional regulators, increased enolase activity, and exercise-induced lactic acidosis. As a consequence, constitutively reduced myostatin signaling diminishes exercise capacity, while the hypermuscular state of Mstn/ mice increases oxygen consumption and the energy cost of running. We wondered whether these results are the mere consequence of the congenital fiber-type switch toward a glycolytic phenotype of constitutive Mstn/ mice. Hence, we overexpressed myostatin propeptide in adult mice, which did not affect fiber-type distribution, while nonetheless causing increased muscle fatigability, diminished exercise capacity, and decreased Pparb/d and Pgc1a expression. In conclusion, our results suggest that myostatin endows skeletal muscle with high oxidative capacity and low fatigability, thus regulating the delicate balance between muscle mass, muscle force, energy metabolism, and endurance capacity

Étude de la coordination des phénotypes contractile et métabolique du muscle strié squelettique à travers des modèles animaux

La fonction principale du muscle étant la contraction, nous avons combiné des évaluations physiologiques, biochimiques et structurelles de la régénération des muscles dans divers modèles de lésions (venin, ischémie et venin). Bien que les critères biochimiques suggèrent une récupération complète, ce n'est pas le cas du point de vue fonctionnel. Nos travaux démontrent donc que l'examen des propriétés contractiles après une lésion est la méthode d'évaluation la plus pertinente pour apprécier le degré de guérison du muscle. De plus, il a été récemment recommandé d'analyser les régulations moléculaires par groupe de gènes fonctionnels ou module (protéines contractiles, mitochondrie, transport ionique, acide gras,...). Dans le but de progresser dans la compréhension des modulations coordonnées survenant dans la plasticité musculaire, nous avons entrepris de caractériser les changements dans les module de gènes correspondant au métabolisme énergétique et aux isoformes des protéines contractiles. Nous avons fait le choix de marqueurs spécifiques des modules dans des modèles animaux où le statut neuromusculaire est modifié soit par une hypodynamie (micro gravité simulée par une suspension) soit par une hyperdynamie (entraînement physique), aussi bien dans des muscles lents que dans de muscles rapides. Pour cela nous avons développé des micro-méthodes pernettant d'obtenir des données sur les changements d'expression de nombreux marqueurs, à partir d'un seul muscle. Nous vaons ainsi développé une analyse des modifications coordonnées par une approche certes globale mais qui reste plus ciblée que les approches protéomiques ou génomiques développées ces dernières années.There exists little information on the functional recovery and the relationships between functional parameters, biochemistry and the structural aspect of the recovery. This is why, we have combined physiological, biochemical and structural evaluations of the regenerating skeletal muscles in various models of lesions (venom, ischemia and venom). Although the biochemical criteria suggest a complete recovery, it is not the case from the functional xiewpoint. Our work thus shows that the examination of the contractile properties after a lesion is the most relevant method of evaluation to appreciate the degree of muscle recovery. It was recently recommended to analyze the molecular regulations by group of functional genes or modules (contractile proteins, mitochondria, ionic, fatty acid or glucose transport, etc). With the aim of progressing in understanding the coordinated modulations governing muscle plasticy, we undertook to characterize changes in gene modules corresponding to energy metabolism and to isoforms of contractile proteins. We chose specific markers of these moduls to study animal models of neuromuscular modifications corresponding to either hypodynamy (microgravity simulated by suspension) or hyperdynamy (training), in slow muscles. For that purpose, we developed micromethods allowing to obtain data on expression changes of many markers, starting from only one muscle. We thus developed an analysis of coordinated modifications, bringing a global perspective, although more restricted than the proteomic or genomic approaches developed these past years.PARIS12-CRETEIL BU Multidisc. (940282102) / SudocSudocFranceF

Application of a force-velocity-endurance model to in situ muscle evaluation in mouse model.

Introduction. The muscular contractile capacity is essential for human and animal movement and locomotion.Owing to their molecular structure, striated skeletal muscle cells produce a force that is a function oftheir rate of shortening. When the force production capacity of the neuromuscular system on an isolated muscleis explored, this relationship can be formulated mathematically by a rational function F(V ) [1]. Moreover, theintensity of this force decreases as a function of the duration F(t), and converges towards a characteristic criticalintensity [2]. The interaction between these two fundamental relationships has been studied only throughindependent comparisons. Considering them as two projections of a single force-velocity-time relationship [3]would make it possible to describe the force production capacities and their interactions in their entirety. Theaim of this conceptual framework is to use an integrative model to unify a new Force-Velocity-Endurance (FVE)relationship that can define muscle properties and fatigability.Methods. This new theoretical framework proposes a model that is a function of two variables (time t andvelocity V ), and seven major parameters to describe muscle properties: initial fatigue-free capacities (initialforce (F0i ), initial velocity (V0i ), initial curvature (Ci) coefficients), critical capacities (F0c , V0c , Cc) and acharacteristic time τ corresponding to the rate of capacity decline. To measure these parameters, a new 3 minall-out test with velocity variation was developed on an isokinetic ergometer (Aurora Scientific 300C) to scanthe maximum capacities of the FVE surface, on both the velocity and time dimensions. The model was testedon 12 wild-type mice (six males and sixfemales) for the tibialis anterior (TA) and gastrocnemius (GA) muscles.Results and discussion. The goodness of fit of the model from the experimental data was excellent for allmuscles (r² > 0.97). The proposed model revealed significant differences between the TA and GA muscle groups.For males, F0i , F0c and τ were higher for GA compared to TA. Considering females, F0i was significantly higherfor GA but relative F0c was higher for TA. This new model also revealed differences in the muscle capacity asa function of sexual dimorphism. For instance, F0i was sgnificanlty higher for males compared to female onlyfor TA but not GA muscles.Conclusions and perspectives. These results demonstrate that it is possible to determine the individualparameters of the proposed model (F0i , V0i , Ci, F0c , V0c , Cc and τ ) from the experimental data obtained fromthe proposed all-out test. Validating the existence of a universal FVE relationship and its theoretical foundationswould open a new conceptual framework for improving our understanding of muscle function. Although thisproject is fundamental, the practical applications resulting from this new framework could be numerous, suchas functional analysis of gene therapy in myology or the impairment of neuromuscular function in patients

Application of a force-velocity-endurance model to in situ muscle evaluation in mouse model.

Introduction. The muscular contractile capacity is essential for human and animal movement and locomotion.Owing to their molecular structure, striated skeletal muscle cells produce a force that is a function oftheir rate of shortening. When the force production capacity of the neuromuscular system on an isolated muscleis explored, this relationship can be formulated mathematically by a rational function F(V ) [1]. Moreover, theintensity of this force decreases as a function of the duration F(t), and converges towards a characteristic criticalintensity [2]. The interaction between these two fundamental relationships has been studied only throughindependent comparisons. Considering them as two projections of a single force-velocity-time relationship [3]would make it possible to describe the force production capacities and their interactions in their entirety. Theaim of this conceptual framework is to use an integrative model to unify a new Force-Velocity-Endurance (FVE)relationship that can define muscle properties and fatigability.Methods. This new theoretical framework proposes a model that is a function of two variables (time t andvelocity V ), and seven major parameters to describe muscle properties: initial fatigue-free capacities (initialforce (F0i ), initial velocity (V0i ), initial curvature (Ci) coefficients), critical capacities (F0c , V0c , Cc) and acharacteristic time τ corresponding to the rate of capacity decline. To measure these parameters, a new 3 minall-out test with velocity variation was developed on an isokinetic ergometer (Aurora Scientific 300C) to scanthe maximum capacities of the FVE surface, on both the velocity and time dimensions. The model was testedon 12 wild-type mice (six males and sixfemales) for the tibialis anterior (TA) and gastrocnemius (GA) muscles.Results and discussion. The goodness of fit of the model from the experimental data was excellent for allmuscles (r² > 0.97). The proposed model revealed significant differences between the TA and GA muscle groups.For males, F0i , F0c and τ were higher for GA compared to TA. Considering females, F0i was significantly higherfor GA but relative F0c was higher for TA. This new model also revealed differences in the muscle capacity asa function of sexual dimorphism. For instance, F0i was sgnificanlty higher for males compared to female onlyfor TA but not GA muscles.Conclusions and perspectives. These results demonstrate that it is possible to determine the individualparameters of the proposed model (F0i , V0i , Ci, F0c , V0c , Cc and τ ) from the experimental data obtained fromthe proposed all-out test. Validating the existence of a universal FVE relationship and its theoretical foundationswould open a new conceptual framework for improving our understanding of muscle function. Although thisproject is fundamental, the practical applications resulting from this new framework could be numerous, suchas functional analysis of gene therapy in myology or the impairment of neuromuscular function in patients

Protective effect of female gender-related factors on muscle force-generating capacity and fragility in the dystrophic mdx mouse

International audienceIntroduction: The dystrophic features in hindlimb skeletal muscles of female mdx mice are unclear. Methods: We analyzed force-generating capacity and force decline after lengthening contraction-induced damage (fragility). Results: Young (6-month-old) female mdx mice displayed reduced force-generating capacity (-18%) and higher fragility (23% force decline) compared with female age-matched wild-type mice. These 2 dystrophic features were less accentuated in young female than in young male mdx mice (-32% and 42% force drop). With advancing age, force-generating capacity decreased and fragility increased in old (20 month) female mdx mice (-21% and 57% force decline), but they were unchanged in old male mdx mice. Moreover, estradiol treatment had no effect in old female mdx mice. Conclusions: Female gender-related factors mitigate dystrophic features in young but not old mdx mice. Further studies are warranted to identify the beneficial gender-related factor in dystrophic muscle. Muscle Nerve, 201

Voluntary Physical Activity Protects from Susceptibility to Skeletal Muscle Contraction-Induced Injury But Worsens Heart Function in mdx Mice

International audienceIt is well known that inactivity/activity influences skeletal muscle physiological characteristics. However, the effects of inactivity/activity on muscle weakness and increased susceptibility to muscle contraction-induced injury have not been extensively studied in mdx mice, a murine model of Duchenne muscular dystrophy with dystrophin deficiency. In the present study, we demonstrate that inactivity (ie, leg immobilization) worsened the muscle weakness and the susceptibility to contraction-induced injury in mdx mice. Inactivity also mimicked these two dystrophic features in wild-type mice. In contrast, we demonstrate that these parameters can be improved by activity (ie, voluntary wheel running) in mdx mice. Biochemical analyses indicate that the changes induced by inactivity/activity were not related to fiber-type transition but were associated with altered expression of different genes involved in fiber growth (GDF8), structure (Actg1), and calcium homeostasis (Stim1 and Jph1). However, activity reduced left ventricular function (ie, ejection and shortening fractions) in mdx, but not C57, mice. Altogether, our study suggests that muscle weakness and susceptibility to contraction-induced injury in dystrophic muscle could be attributable, at least in part, to inactivity. It also suggests that activity exerts a beneficial effect on dystrophic skeletal muscle but not on the heart

Advances in the understanding of skeletal muscle weakness in murine models of diseases affecting nerve-evoked muscle activity, motor neurons, synapses and myofibers

International audienceDisease processes and trauma affecting nerve-evoked muscle activity, motor neurons, synapses and myofibers cause different levels of muscle weakness, i.e., reduced maximal force production in response to voluntary activation or nerve stimulation. However, the mechanisms of muscle weakness are not well known. Using murine models of amyotrophic lateral sclerosis (SOD1(G93) transgenic mice), congenital myasthenic syndrome (AChE knockout mice and Musk(V789m/-) mutant mice), Schwartz Jampel syndrome (Hspg2(C1532YNEO/C1532YNEO) mutant mice) and traumatic nerve injury (Neurotomized wild-type mice), we show that the reduced maximal activation capacity (the ability of the nerve to maximally activate the muscle) explains 52%, 58% and 100% of severe weakness in respectively SOD1(G93A), Neurotomized and Musk mice, whereas muscle atrophy only explains 37%, 27% and 0%. We also demonstrate that the impaired maximal activation capacity observed in SOD 1, Neurotomized, and Musk mice is not highly related to Hdac4 gene upregulation. Moreover, in SOD1 and Neurotomized mice our results suggest LC3, Fn14, Bcl3 and Gadd45a as candidate genes involved in the maintenance of the severe atrophic state. In conclusion, our study indicates that muscle weakness can result from the triggering of different signaling pathways. This knowledge may be helpful in designing therapeutic strategies and finding new drug targets for amyotrophic lateral sclerosis, congenital myasthenic syndrome, Schwartz Jampel syndrome and nerve injury

Necroptosis mediates myofibre death in dystrophin-deficient mice

Muscular dystrophies are characterised by extensive myofibre cell death. Here Morgan et al. show that RIPK3-mediated necroptosis contributes to myofibre cell death in Duchenne muscular dystrophy, and that RIPK3 deletion protects dystrophic mice against myofibre degeneration

Targeting myostatin to improve skeletal muscle mass and function in a mouse model of Dnm2-related centronuclear myopathy

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