Biology subjects

Gervais, M.

Publications and source records attributed to Gervais, M..

6 recordsLinked to original sources

bioRxiv2026

Metabolic Heterogeneity of Muscle Stem Cells is Controlled by the Myofiber Niche

Metabolic pathways support biomass synthesis and provide substrates for epigenetic modifications of histones and DNA. These findings are particularly relevant for adult stem cells, where metabolic changes significantly impact functional behavior. However, assessing the metabolism of these cells in their native microenvironment is challenging as this typically necessitates dissociation prior to metabolic analysis. In this study, we focus on muscle stem cells (MuSCs) and show that removing these cells from the niche significantly alters their metabolic profile. To overcome this issue, we developed a novel enzymatic staining method for in situ metabolic profiling at a single-cell resolution. This approach reveals unexpected metabolic heterogeneity of MuSCs, identifying oxidative and glycolytic subsets, and demonstrates that their metabolism is directly modulated by adjacent myofibers. Accordingly, perturbing myofiber metabolism remodels the MuSC niche and drives metabolic adaptation in MuSCs. Finally, we define the kinetics by which myofiber-dependent metabolic regulation of MuSCs is re-established during muscle regeneration, thereby revealing how niche-imposed metabolic cues shape stem cell identity in vivo.

physiology↗

bioRxiv2024

Targeted-SMN insufficiency in Skeletal Muscle Stem Cells mediates non-cell autonomous loss of motor neurons at long term

Spinal Muscular Atrophy (SMA) is due to a deficit in SMN protein encoded by the SMN1 gene. SMN-targeted disease modifying treatments have greatly improved the clinical outcomes of this neuromuscular disease. However, uncertainties remain regarding their long-term efficacy and non-neuronal tissue involvement in disease progression. We found that SMA type II patient muscles display a reduced number of quiescent PAX7+ Muscle Stem Cells (MuSC). In SMA mice, we showed that SMN is an important regulator of myogenic progenitor fate during early postnatal growth. In Pax7 Cre-driven conditional knockout mouse models, we demonstrated that high levels of SMN are required to ensure the maintenance of the quiescent MuSC pool in adult muscle. We further established that depletion of SMN-deficient MuSC yielded neuromuscular junctions remodeling followed by a non-cell autonomous loss of motor neurons in the long term. Overall, our findings demonstrate that MuSC are a crucial therapeutic target for SMA treatment. HIGHLIGHTSO_LISMN regulates myogenic lineage progression and quiescent MuSC pool establishment during postnatal growth C_LIO_LIBoth Smn alleles are necessary for the survival of quiescent MuSC in adult muscle C_LIO_LIDepletion of SMN-deficient MuSC leads to NMJ remodeling and non-cell autonomous loss of MN C_LI

pathology↗

bioRxiv2024

Transient hypoxia followed by progressive reoxygenation is required for efficient skeletal muscle repair through Rev-ERBalpha modulation

Muscle stem cells (MuSCs) are essential for skeletal muscle repair. Following injury, MuSCs reside in low oxygen environments until muscle fibers and vascularization are restablished. The dynamics of oxygen levels during the regenerative process and its impact on muscle repair has been underappreciated. We confirm that muscle repair is initiated in a low oxygen environment followed by gradual reoxygenation. Strikingly, when muscle reoxygenation is limited by keeping mice under systemic hypoxia, muscle repair is impaired and leads to the formation of hypotrophic myofibers. In vivo, sustained hypoxia decreases the ability of MuSCs to differentiate and fuse independently of HIF-1. Prolonged hypoxia specifically affects the circadian clock by increasing Rev-erb expression in MuSCs. Using pharmacological tools, we demonstrate that Rev-ERB negatively regulates myogenesis by reducing late myogenic cell fusion under prolonged hypoxia. Our results underscore the critical role of progressive muscle reoxygenation after transient hypoxia in coordinating proper myogenesis through Rev-ERB.

physiology↗

bioRxiv2022

Receptor interacting protein kinase-3 promotes both myopathy and cardiomyopathy in dystrophin-deficient mice

BackgroundDuchenne muscular dystrophy (DMD) is a progressive muscle degenerative disorder, culminating in a complete loss of ambulation, hypertrophic cardiomyopathy and a fatal cardiorespiratory failure. Necroptosis is the form of necrosis that is dependent upon the receptor-interacting protein kinase (RIPK) 3; it is involved in several inflammatory and neurodegenerative conditions. We previously identified RIPK3 as a key player in the acute myonecrosis affecting the hindlimb muscles of the dystrophic mouse model, mdx. Whether necroptosis also mediates respiratory and heart disorders in DMD is currently unknown. MethodsEvidence of activation of the necroptotic axis was examined in dystrophic tissues from Golden retriever muscular dystrophy (GRMD) dogs and R-DMDdel52 rats. A functional assessment of the involvement of necroptosis in dystrophic animals was performed on mdx mice that were genetically depleted for RIPK3. Dystrophic mice aged from 12 to 18 months were analyzed by histology and molecular biology to compare the phenotype of muscles from mdxRipk3+/+ and mdxRipk3-/- mice. Heart function was also examined by echocardiography in 40-week-old mice. ResultsQuantification of RIPK3 transcripts in sartorius and biceps femoris muscles from GRMD dogs positively correlated to myonecrosis levels (r=0.81; p=0.0076). RIPK3 was also found elevated in the diaphragm (p=0<0.05). In the slow progressing heart phenotype of GRMD dogs, the phosphorylated form of RIPK1 at the Serine 161 site was dramatically increased in cardiomyocytes. A similar p-RIPK1 upregulation characterized the cardiomyocytes of R-DMDdel52 rats, associated with a marked overexpression of Ripk1 (p=0.007) and Ripk3 (p=0.008), indicating primed activation of the necroptotic pathway in the dystrophic heart. MdxRipk3-/- mice displayed decreased compensatory hypertrophy of the heart (p=0.014), and echocardiography showed a 19% increase in the relative wall thickness (p<0.05) and 29% reduction in the left ventricle mass (p=0.0144). Besides, mdxRipk3-/- mice presented no evidence of a regenerative default or sarcopenia in skeletal muscles, moreover around 50% less affected by fibrosis (p<0.05). ConclusionsOur data provide evidence of the activation of the necroptotic pathway in degenerative tissues from dystrophic animal models, including the diaphragm and the heart. The genetic inhibition of necroptosis in dystrophic mice improves both cardiac function and histological features of muscles, suggesting that prevention of necroptosis is susceptible to providing multiorgan beneficial effects for DMD.

cell biology↗

bioRxiv2021

Interferon-gamma mediates skeletal muscle lesions through JAK/STAT pathway activation in inclusion body myositis

Dysimmune and Inflammatory Myopathies (DIMs) are acquired idiopathic myopathy associated with immune response dysregulation. Inclusion Body Myositis (IBM), the most common DIMs, is characterized by endomysial infiltrates of cytotoxic T lymphocytes CD8, muscle type II-interferon (IFN{gamma}) signature, and by the lack of response to immunomodulatory therapies. We showed that IBM was pathologically characterized by the presence of chronic degenerative myopathic features including myofiber atrophy, fibrosis, adipose involution, and the altered functions of skeletal muscle stem cells. Here, we demonstrated that protracted systemic exposure to IFN{gamma} delayed muscle regeneration and led to IBM-like muscular degenerative changes in mice. In vitro, IFN{gamma} treatment inhibited the activation, proliferation, migration, differentiation, and fusion of myogenic progenitor cells and promoted their senescence through JAK-STAT-dependent activation. Finally, JAK-STAT inhibitor, ruxolitinib abrogated the deleterious effects of IFN{gamma} on muscle regeneration, suggesting that the JAK-STAT pathway could represent a new therapeutic target for IBM.

cell biology↗

bioRxiv2020

EphrinB1 modulates glutamatergic inputs into POMC neurons and controls glucose homeostasis

Proopiomelanocortin (POMC) neurons are major regulators of energy balance and glucose homeostasis. In addition to being regulated by hormones and nutrients, POMC neurons are controlled by glutamatergic input originating from multiple brain regions. However, the factors involved in the formation of glutamatergic inputs and how they contribute to bodily functions remain largely unknown. Here, we show that during the development of glutamatergic inputs, POMC neurons exhibit enriched expression of the Efnb1 (EphrinB1) and Efnb2 (EphrinB2) genes, which are known to control excitatory synapse formation. In vitro silencing and in vivo loss of Efnb1 or Efnb2 in POMC neurons decreases the amount of glutamatergic inputs into these neurons. We found that mice lacking Efnb1 in POMC neurons display impaired glucose tolerance due to blunted vagus nerve activity and decreased insulin secretion. However, mice lacking Efnb2 in POMC neurons showed no deregulation of insulin secretion and only mild alterations in feeding behavior and gluconeogenesis. Collectively, our data demonstrate the role of ephrins in controlling excitatory input amount into POMC neurons and show an isotype-specific role of ephrins on the regulation of glucose homeostasis and feeding.

physiology↗