Genetic and Pharmacologic Inhibition of Myostatin Restores Muscle Mass in a Dynamin 2 ‐Related Centronuclear Myopathy Mouse Model
Abstract
BACKGROUND: Autosomal dominant centronuclear myopathy (ADCNM), most commonly caused by mutations in the dynamin 2 (DNM2) gene, is a rare congenital myopathy characterized by progressive muscle weakness and atrophy. Myostatin, a key negative regulator of skeletal muscle mass, has shown therapeutic potential in several models of neuromuscular diseases. We hypothesized that inhibiting myostatin could counteract muscle deconditioning in ADCNM and evaluated the therapeutic potential of both genetic and pharmacological myostatin inhibition strategies in a mouse model of ADCNM. METHODS: twice weekly starting at 4 weeks of age for 4 weeks. Muscle structure, molecular pathways and functional analysis were performed in tibialis anterior muscle. RESULTS: MRI and immunohistochemical analyses showed that KI mice exhibited impaired postnatal muscle growth between 1 and 2 months of age, resulting in persistent muscle hypotrophy (-15%, p < 0.05). This defect was associated with a significant reduction in the number of satellite cells (-53%, p < 0.001 at 1 month and -68%, p < 0.01 at 2 months), the central accumulation of dense NADH-TR staining in more than 20% of muscle fibres, an upregulation of atrophy-related E3 ligases mRNA (Trim63 + 50%, p < 0.001 and +87%, p < 0.001; Fbxo32 + 39% p < 0.05 and +95%, p < 0.001 at 1 and 2 months of age, respectively) and impaired autophagy. Genetic deletion of myostatin in KIKO mice fully restored muscle mass and normalized muscle function to wild-type conditions. Pharmacological inhibition with sActRIIB-Fc also robustly restored muscle mass to wild-type values, primarily via activation of the Akt-mTOR pathway. However, this anabolic effect was transient, as muscle mass returned to baseline 5 weeks after treatment cessation. Importantly, despite increased muscle mass, sActRIIB-Fc treatment did not improve muscle force and key pathological features, including defects in proteostasis, mitochondrial organization and excitation-contraction coupling. CONCLUSIONS: These findings establish the proof of concept that myostatin inhibition counteracts skeletal muscle growth defect in ADCNM, which may be combined with other drugs to better address the multifactorial nature of muscle weakness in ADCNM.
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BibTeX
@article{durieux2026genetic,
title = {{Genetic and Pharmacologic Inhibition of Myostatin Restores Muscle Mass in a Dynamin 2 ‐Related Centronuclear Myopathy Mouse Model}},
author = {Anne-Cécile Durieux and David Arnould and Mathias Velarde and Laurent Schaeffer and Damien Freyssenet and Valentine Allibert and Chloé Paret and Quentin Debelley and Esra Kizilkilic and Sidney Chambon and Emmanuelle Girard and Louise Collin and Alexandre Gensel and Josiane Castells and Aja Pasternack and Maximilien Bowen and Baptiste Morel and Christophe Hourdé and Olli Ritvos and Marc Bitoun and Rémi Mounier},
journal = {Journal of Cachexia, Sarcopenia and Muscle},
year = {2026},
month = sep,
doi = {10.1002/jcsm.70338},
url = {https://hal.science/hal-05746993v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Genetic and Pharmacologic Inhibition of Myostatin Restores Muscle Mass in a Dynamin 2 ‐Related Centronuclear Myopathy Mouse Model
AU - Anne-Cécile Durieux
AU - David Arnould
AU - Mathias Velarde
AU - Laurent Schaeffer
AU - Damien Freyssenet
AU - Valentine Allibert
AU - Chloé Paret
AU - Quentin Debelley
AU - Esra Kizilkilic
AU - Sidney Chambon
AU - Emmanuelle Girard
AU - Louise Collin
AU - Alexandre Gensel
AU - Josiane Castells
AU - Aja Pasternack
AU - Maximilien Bowen
AU - Baptiste Morel
AU - Christophe Hourdé
AU - Olli Ritvos
AU - Marc Bitoun
AU - Rémi Mounier
PY - 2026
DA - 2026/09/11
JO - Journal of Cachexia, Sarcopenia and Muscle
DO - 10.1002/jcsm.70338
UR - https://hal.science/hal-05746993v1
AB - BACKGROUND: Autosomal dominant centronuclear myopathy (ADCNM), most commonly caused by mutations in the dynamin 2 (DNM2) gene, is a rare congenital myopathy characterized by progressive muscle weakness and atrophy. Myostatin, a key negative regulator of skeletal muscle mass, has shown therapeutic potential in several models of neuromuscular diseases. We hypothesized that inhibiting myostatin could counteract muscle deconditioning in ADCNM and evaluated the therapeutic potential of both genetic and pharmacological myostatin inhibition strategies in a mouse model of ADCNM. METHODS: twice weekly starting at 4 weeks of age for 4 weeks. Muscle structure, molecular pathways and functional analysis were performed in tibialis anterior muscle. RESULTS: MRI and immunohistochemical analyses showed that KI mice exhibited impaired postnatal muscle growth between 1 and 2 months of age, resulting in persistent muscle hypotrophy (-15%, p < 0.05). This defect was associated with a significant reduction in the number of satellite cells (-53%, p < 0.001 at 1 month and -68%, p < 0.01 at 2 months), the central accumulation of dense NADH-TR staining in more than 20% of muscle fibres, an upregulation of atrophy-related E3 ligases mRNA (Trim63 + 50%, p < 0.001 and +87%, p < 0.001; Fbxo32 + 39% p < 0.05 and +95%, p < 0.001 at 1 and 2 months of age, respectively) and impaired autophagy. Genetic deletion of myostatin in KIKO mice fully restored muscle mass and normalized muscle function to wild-type conditions. Pharmacological inhibition with sActRIIB-Fc also robustly restored muscle mass to wild-type values, primarily via activation of the Akt-mTOR pathway. However, this anabolic effect was transient, as muscle mass returned to baseline 5 weeks after treatment cessation. Importantly, despite increased muscle mass, sActRIIB-Fc treatment did not improve muscle force and key pathological features, including defects in proteostasis, mitochondrial organization and excitation-contraction coupling. CONCLUSIONS: These findings establish the proof of concept that myostatin inhibition counteracts skeletal muscle growth defect in ADCNM, which may be combined with other drugs to better address the multifactorial nature of muscle weakness in ADCNM.
SN - 2190-5991
SN - 2190-6009
ER -