Blocking Myostatin Rebuilds Wasted Muscle in Dynamin 2 Myopathy Mice, But Power Lags Behind

A rare congenital muscle disease that robs patients of strength from childhood has long lacked meaningful treatment options, but a new preclinical study offers a striking proof of concept: switching off a single molecular brake on muscle growth can restore much of the muscle mass lost to the disease. The catch, researchers found, is that bigger muscles do not automatically mean stronger muscles, a nuance that could shape how future therapies for centronuclear myopathy are designed and evaluated.

Centronuclear myopathies are a group of rare inherited disorders defined by progressive muscle wasting and weakness, named for the abnormal positioning of nuclei at the centre of muscle fibres rather than at their periphery. The most common autosomal dominant form is caused by mutations in the DNM2 gene, which encodes dynamin 2, a GTPase enzyme involved in membrane fission, intracellular trafficking and organelle morphology. Roughly 40 different heterozygous DNM2 mutations have been linked to the disease, which accounts for approximately 15 percent of all centronuclear myopathy cases. Severity ranges broadly, from mild late-onset weakness to severe neonatal forms, and no curative therapy currently exists.

In a study published in the Journal of Cachexia, Sarcopenia and Muscle, a research team used the KI-Dnm2 R465W/+ mouse model, which carries a disease-causing mutation analogous to those found in patients, to test whether inhibiting myostatin could counteract the muscle deterioration characteristic of the disease. Myostatin, also known as growth differentiation factor 8, is widely regarded as the master negative regulator of skeletal muscle mass throughout development and adult life. It signals through the activin type IIB receptor, activating the SMAD2/3 pathway, which suppresses the proliferation and differentiation of muscle precursor cells, represses the IGF1-Akt-mTOR anabolic pathway, downregulates muscle-specific genes and promotes E3 ubiquitin ligases involved in protein degradation.

The researchers first mapped the natural course of the disease in these mice using longitudinal magnetic resonance imaging, repeated at 1, 2 and 8 months of age with a high-field 7-Tesla system. Although the knockin mice were viable and grew normally in body size, their leg muscle cross-sectional area lagged dramatically behind healthy littermates. Between 1 and 2 months of age, a critical postnatal growth window, healthy mice expanded their leg muscle cross-sectional area by 1.5-fold, while the mutant mice managed only a 1.2-fold increase. Functional testing revealed that the trouble began even earlier: impaired motor coordination and reduced grip strength were already detectable at 1 month, before measurable muscle growth failure appeared, and histological analysis of the tibialis anterior muscle showed more than 20 percent of fibres displaying the hallmark central NADH-TR staining pattern of the disease at 2 months.

Digging into the molecular roots of this growth failure, the team found a coordinated disruption of multiple homeostatic systems. The number of Pax7-positive satellite cells, the stem-like reservoir that fuses with growing fibres to supply new myonuclei, was significantly reduced, along with MyoD expression, indicating defective myonuclear accretion. At the same time, the translational repressor Eif4ebp1 was upregulated, suggesting suppressed protein synthesis, while FOXO3 and its downstream E3 ligase targets MuRF1, Atrogin-1 and Musa1 were elevated, pointing to accelerated protein breakdown. Autophagy-related transcripts such as Bnip3 and Map1lc3b were paradoxically reduced while P62 and LC3B-I protein accumulated, a signature of impaired autophagic flux. Together, these findings paint centronuclear myopathy not as a single broken pathway but as a global collapse of muscle protein and nuclear homeostasis.

To test whether myostatin was a viable therapeutic target, the researchers crossed the mutant mice with a myostatin knockout line, producing double-mutant animals completely lacking functional myostatin. The results were dramatic. The double-mutant mice gained substantially more body weight, and the mass of the tibialis anterior, quadriceps, extensor digitorum longus and soleus muscles far exceeded even healthy wild-type levels. Critically, grip strength and rotarod performance, which were significantly impaired in the myopathy mice, were fully restored to normal. Because myostatin is absent from embryogenesis onward in these animals, lifelong suppression appears to be integrated into developmental muscle growth programs, including enhanced satellite cell activation and myoblast proliferation, producing stable structural and functional benefits.

Genetic deletion, however, is not a practical option for patients, so the team next turned to pharmacology. They administered a soluble activin type IIB receptor fused to a human IgG1 Fc fragment, a decoy receptor that sequesters both myostatin and activin A in the circulation, by intraperitoneal injection twice weekly at a dose of 5 milligrams per kilogram. Four-week-old mutant mice received the treatment for four consecutive weeks. The intervention produced a marked anabolic effect: tibialis anterior mass was partially restored, quadriceps mass was completely normalized, and gastrocnemius mass actually exceeded wild-type values by the end of treatment. Serum myostatin concentrations rose during therapy, consistent with the decoy receptor prolonging the circulating half-life of the bound hormone and with increased production from newly expanded muscle mass.

But the pharmacological results came with two sobering caveats. First, the muscle gains proved entirely reversible: five weeks after treatment stopped, muscle mass had fallen back to untreated disease levels, indicating that continuous administration would be required to maintain any benefit. Second, and perhaps more importantly, the drug restored size without restoring power. In situ force measurements of the tibialis anterior showed no improvement in maximal absolute or specific force despite the hypertrophy. Molecular analysis explained why: while Akt Ser473 phosphorylation increased, confirming an anabolic signal, the treatment failed to correct the core pathological features of the disease, including elevated E3 ligase expression, impaired autophagic flux, reduced ribosomal and myosin heavy chain transcripts, and dysregulated expression of excitation-contraction coupling genes such as Chrna1, RyR1 and Casq1. Because dynamin 2 is known to organize transverse tubules, the membrane invaginations that transmit electrical signals deep into the fibre, these contractile defects appear intrinsic to the disease and beyond the reach of simply growing bigger fibres.

The contrast between the two strategies carries a clear message for the field. In mice, permanent myostatin inactivation reshapes developmental programs and delivers lasting improvements in both mass and function, whereas transient pharmacological blockade produces short-lived hypertrophy that leaves the underlying contractile and metabolic defects untouched. The authors note that combined myostatin and activin A inhibition may hold particular promise for human medicine, since activin A circulates at higher levels in people than in mice and signals through the same SMAD2/3 axis. Their conclusion is that future therapies for autosomal dominant centronuclear myopathy should be judged not merely by their ability to bulk up muscle, but by whether they durably restore contractile performance, likely in combination with approaches that directly repair the excitation-contraction machinery. The work was supported by AFM-Téléthon through the strategic MyoNeurALP programme.

Subject of Research: Myostatin inhibition therapy for dynamin 2-related centronuclear myopathy

Article Title: Genetic and Pharmacologic Inhibition of Myostatin Restores Muscle Mass in a Dynamin 2‐Related Centronuclear Myopathy Mouse Model

Article References: Anne‐Cécile, D., David, A., Mathias, V., Valentine, A., Chloé, P., Quentin, D., Esra, K., Sidney, C., Emmanuelle, G., Louise, C., Alexandre, G., Josiane, C., Aja, P., Maximilien, B., Baptiste, M., Christophe, H., Schaeffer, L., Olli, R., Marc, B., … Damien, F. (2026). Genetic and Pharmacologic Inhibition of Myostatin Restores Muscle Mass in a Dynamin 2 ‐Related Centronuclear Myopathy Mouse Model. Journal of Cachexia, Sarcopenia and Muscle, 17(5), Article e70338. https://doi.org/10.1002/jcsm.70338

Image Credits: AI Generated

DOI: 10.1002/jcsm.70338

Keywords: centronuclear myopathy, myostatin, dynamin 2, sActRIIB-Fc, muscle mass, muscle force, satellite cells, autophagy, excitation-contraction coupling, mouse model, neuromuscular disease, Akt signalling