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 Knockin‐ dnm2 R465W/+ (KI) mice were first crossed with knockout‐ myostatin mice (KO) to generate double mutant (KIKO) mice carrying both the R465W missense mutation and the myostatin gene deletion. In a second experiment, KI mice received intraperitoneal injections of a soluble activin type IIB receptor fused to IgG1 Fc fragment (sActRIIB‐Fc) at 5 mg kg −1 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  p  p  Trim63  + 50%, p  and +87%, p  ; Fbxo32 + 39% p  and +95%, p  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.