Six Homeoproteins and a Iinc-RNA at the Fast MYH Locus Lock Fast Myofiber Terminal Phenotype

International audienceThousands of long intergenic non-coding RNAs (lincRNAs) are encoded by the mammalian genome. However, the function of most of these lincRNAs has not been identified in vivo. Here, we demonstrate a role for a novel lincRNA, linc-MYH, in adult fast-type myofiber specialization. Fast myosin heavy chain (MYH) genes and linc-MYH share a common enhancer, located in the fast MYH gene locus and regulated by Six1 homeoproteins. linc-MYH in nuclei of fast-type myofibers prevents slow-type and enhances fast-type gene expression. Functional fast-sarcomeric unit formation is achieved by the coordinate expression of fast MYHs and linc-MYH, under the control of a common Six-bound enhancer

Automatic solver for non-linear partial differential equations with implicit local laws: Application to unilateral contact

International audienceIn general, non-linear continuum mechanics combine global balance equations and local constitutive laws. In this work, frictionless contact between a rigid tool and a thin elastic shell is considered. This class of boundary value problems involves two non-linear algebraic laws: the first one gives explicitly the stress field as a function of the strain throughout the continuum part, whereas the second one is a non-linear equation relating the contact forces and the displacement at the boundary.Given the fact that classical computational approaches sometimes require significant effort in implementation of complex non-linear problems, a computation technique based on automatic differentiation of constitutive laws is presented in this paper. The procedure enables to compute automatically the higher-order derivatives of these constitutive laws and thereafter to define the Taylor series that are the basis of the continuation technique called asymptotic numerical method. The algorithm is about the same with an explicit or implicit constitutive relation. In the modelling of forming processes, many tool shapes can be encountered. The presented computational technique permits an easy implementation of these complex surfaces, for instance in a finite element code : the user is only required to define the tool geometry and the computer is able to obtain the higher-order derivatives

Muscle PGC-1α modulates satellite cell number and proliferation by remodeling the stem cell niche

BACKGROUND: The myogenic capacity of satellite cells (SCs), adult muscle stem cells, is influenced by aging, exercise, and other factors. In skeletal muscle, the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a key regulator of oxidative metabolism and endurance training adaptation. However, a link between PGC-1α and SC behavior remains unexplored. METHODS: We have now studied SC function in a PGC-1α fiber-specific gain-of-function animal model. RESULTS: In surprising contrast to bona fide exercise, muscle-specific PGC-1α transgenic mice have lower SC numbers. Nevertheless, SCs from these mice have a higher propensity for activation and proliferation. Intriguingly, muscle PGC-1α triggers a remodeling of the SC niche by altering the extracellular matrix composition, including the levels of fibronectin, which affects the proliferative output of SCs. CONCLUSIONS: Taken together, PGC-1α indirectly affects SC plasticity in skeletal muscle and thereby might contribute to improved SC activation in exercise

Aged Nicotinamide Riboside Kinase 2 Deficient Mice Present an Altered Response to Endurance Exercise Training

Background: Skeletal muscle aging is marked by the development of a sarcopenic phenotype, a global decline of muscle energetic capacities, and an intolerance to exercise. Among the metabolic disorders involved in this syndrome, NAD metabolism was shown to be altered in skeletalmuscle, with an important role for the NAMPT enzyme recycling the nicotinamide precursor. An alternative pathway for NAD biosynthesis has been described for the nicotinamide riboside vitamin B3 precursor used by the NMRK kinases, including the striated muscle-specific NMRK2.Aim: With this study, our goal is to explore the ability of 16-month-old Nmrk2−/− mice to perform endurance exercise and study the consequences on muscle adaptation to exercise.Methods: 10 control and 6 Nmrk2−/− mice were used and randomly assigned to sedentary and treadmill endurance training groups. After 9 weeks of training, heart and skeletal muscle samples were harvested and used for gene expression analysis, NAD levels measurements and immunohistochemistry staining.Results: Endurance training triggered a reduction in the expression of Cpt1b and AcadL genes involved in fatty acid catabolism in the heart of Nmrk2−/− mice, not in control mice. NAD levels were not altered in heart or skeletal muscle, nor at baseline neither after exercise training in any group. Myh7 gene encoding for the slow MHC-I was more strongly induced by exercise in Nmrk2−/− mice than in controls. Moreover, IL-15 expression levels is higher in Nmrk2−/− mice skeletal muscle at baseline compared to controls. No fiber type switch was observed in plantaris after exercise, but fast fibers diameter was reduced in aged control mice, not in Nmrk2−/− mice. No fiber type switch or diameter modification was observed in soleus muscle.Conclusion: In this study, we demonstrated for the first time a phenotype in old Nmrk2−/− mice in response to endurance exercise training. Although NMRK2 seems to be predominantly dispensable to maintain global NAD levels in heart and skeletal muscle, we demonstrated a maladaptive metabolic response to exercise in cardiac and skeletal muscle, showing that NMRK2 has a specific and restricted role in NAD signaling compared to the NAMPT pathway

PGC-1alpha modulates necrosis, inflammatory response, and fibrotic tissue formation in injured skeletal muscle

BACKGROUND: Skeletal muscle tissue has an enormous regenerative capacity that is instrumental for a successful defense against muscle injury and wasting. The peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) exerts therapeutic effects in several muscle pathologies, but its role in damage-induced muscle regeneration is unclear. METHODS: Using muscle-specific gain- and loss-of-function models for PGC-1alpha in combination with the myotoxic agent cardiotoxin (CTX), we explored the role of this transcriptional coactivator in muscle damage and inflammation. RESULTS: Interestingly, we observed PGC-1alpha-dependent effects at the early stages of regeneration, in particular regarding macrophage accumulation and polarization from the pro-inflammatory M1 to the anti-inflammatory M2 type, a faster resolution of necrosis and protection against the development of fibrosis after multiple CTX-induced injuries. CONCLUSIONS: PGC-1alpha exerts beneficial effects on muscle inflammation that might contribute to the therapeutic effects of elevated muscle PGC-1alpha in different models of muscle wasting

Gonad-related factors promote muscle performance gain during postnatal development in male and female mice

To better define the role of male and female gonad-related factors (MGRF, presumably testosterone, and FGRF, presumably estradiol, respectively) on mouse hindlimb skeletal muscle contractile performance/function gain during postnatal development, we analyzed the effect of castration initiated before puberty in male and female mice. We found that muscle absolute and specific (normalized to muscle weight) maximal forces were decreased in 6-mo-old male and female castrated mice compared with age- and sex-matched intact mice, without alteration in neuromuscular transmission. Moreover, castration decreased absolute and specific maximal powers, another important aspect of muscle performance, in 6-mo-old males, but not in females. Absolute maximal force was similarly reduced by castration in 3-mo-old muscle fiber androgen receptor (AR)-deficient and wild-type male mice, indicating that the effect of MGRF was muscle fiber AR independent. Castration reduced the muscle weight gain in 3-mo mice of both sexes and in 6-mo females but not in males. We also found that bone morphogenetic protein signaling through Smad1/5/9 was not altered by castration in atrophic muscle of 3-mo-old mice of both sexes. Moreover, castration decreased the sexual dimorphism regarding muscle performance. Together, these results demonstrated that in the long term, MGRF and FGRF promote muscle performance gain in mice during postnatal development, independently of muscle growth in males, largely via improving muscle contractile quality (force and power normalized), and that MGFR and FGRF also contribute to sexual dimorphism. However, the mechanisms underlying MGFR and FGRF actions remain to be determined

Abnormal splicing switch of DMD's penultimate exon compromises muscle fibre maintenance in myotonic dystrophy

International audienceMyotonic Dystrophy type 1 (DM1) is a dominant neuromuscular disease caused by nuclear-retained RNAs containing expanded CUG repeats. These toxic RNAs alter the activities of RNA splicing factors resulting in alternative splicing misregulation and muscular dysfunction. Here we show that the abnormal splicing of DMD exon 78 found in dystrophic muscles of DM1 patients is due to the functional loss of MBNL1 and leads to the re-expression of an embryonic dystrophin in place of the adult isoform. Forced expression of embryonic dystrophin in zebrafish using an exon-skipping approach severely impairs the mobility and muscle architecture. Moreover, reproducing Dmd exon 78 missplicing switch in mice induces muscle fibre remodelling and ultrastructural abnormalities including ringed fibres, sarcoplasmic masses or Z-band disorganization, which are characteristic features of dystrophic DM1 skeletal muscles. Thus, we propose that splicing misregulation of DMD exon 78 compromises muscle fibre maintenance and contributes to the progressive dystrophic process in DM

Les avancées de la recherche dans le domaine de la modélisation des interactions sol-arbre

Les outils de modélisation au service de la politique, de la planification et de la gestion forestière ne permettent pas encore une évaluation simultanée de l’impact des changements globaux et de la gestion sur les différentes fonctions écologiques et productives assurées par les écosystèmes forestiers. Nous proposons un état des lieux des modèles disponibles dans les différentes disciplines que sont la dendrométrie, l’écophysiologie et les sciences du sol et comment l’intégration des concepts de ces trois disciplines peut permettre d’élaborer les outils nécessaires au gestionnaire. In fine, ces nouveaux outils devront être suffisamment complets pour répondre à des questions à l’échelle de l’écosystème ; distinguer ce qui relève du processus générique de ce qui reste site-dépendant ; permettre de définir puis simuler des scénarios de gestion variés et innovants en environnement incertain, avec des contraintes de plus en plus fortes ; et être documentés et référencés pour garantir leur pérennité et leur utilisation

Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy

Mammalian target of rapamycin (mTOR) is a key regulator of cell growth that associates with raptor and rictor to form the mTOR complex 1 (mTORC1) and mTORC2, respectively. Raptor is required for oxidative muscle integrity, whereas rictor is dispensable. In this study, we show that muscle-specific inactivation of mTOR leads to severe myopathy, resulting in premature death. mTOR-deficient muscles display metabolic changes similar to those observed in muscles lacking raptor, including impaired oxidative metabolism, altered mitochondrial regulation, and glycogen accumulation associated with protein kinase B/Akt hyperactivation. In addition, mTOR-deficient muscles exhibit increased basal glucose uptake, whereas whole body glucose homeostasis is essentially maintained. Importantly, loss of mTOR exacerbates the myopathic features in both slow oxidative and fast glycolytic muscles. Moreover, mTOR but not raptor and rictor deficiency leads to reduced muscle dystrophin content. We provide evidence that mTOR controls dystrophin transcription in a cell-autonomous, rapamycin-resistant, and kinase-independent manner. Collectively, our results demonstrate that mTOR acts mainly via mTORC1, whereas regulation of dystrophin is raptor and rictor independent