Age-Dependent Effect of Myostatin Blockade in the mdx Mouse Model of Duchenne Muscular Dystrophy (DMD)

Myostatin (GDF8) is a member of the transforming growth factor-β (TGF-β) superfamily. Myostatin gene mutations or inhibition of the Myostatin/Activin pathway results in increased skeletal muscle mass, demonstrating its role as a negative regulator of skeletal muscle. Myostatin blockade is a promising strategy for increasing muscle mass in myopathies such as Duchenne Muscular Dystrophy (DMD); however, it faces considerable challenges in clinical translation, in part due to the progressive nature of the disease. Here we tested the ability of JA16 monoclonal antibody-mediated myostatin blockade to improve the dystrophic phenotype in newborn mdx mice (an animal model of DMD). Myostatin inhibition led to significant increases in muscle size, fiber number and cross-sectional area along with increased absolute force alongside reduced post-eccentric contraction force drop and reduced serum creatine kinase. We used the Multiparametric Muscle Improvement Score (MMIS) to objectively quantitate benefits in this preclinical study and determined that the magnitude of improvements exceeded those reported using the exact same intervention in older mdx mice treated for the same duration. This study demonstrates an age-dependent aspect of this intervention and suggests that earlier interventions may provide greater therapeutic benefits.