Anti-Receptor Activator of Nuclear Factor-κB Ligand Improves Muscle Dysfunction and Strengthens Bone in Laminin-α2-Deficient dy2J/dy2J Dystrophic Mice.

Congenital muscular dystrophy type 1A (CMD1A) is a severe genetic neuromuscular disorder caused by mutations in the LAMA2 gene, which encodes the laminin-α2 subunit, an essential structural protein for maintaining muscle integrity during contraction. Affected children experience progressive muscle damage, hypotonia, delayed motor development, and respiratory tract insufficiency. CMD1A muscles undergo repeated cycles of degeneration and regeneration accompanied by chronic inflammation. Beyond its established role in bone remodeling, the receptor activator of nuclear factor-κB/receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin signaling axis has also been implicated in muscle pathophysiology. A 10-day treatment with full-length osteoprotegerin fused to an Fc fragment was previously shown to restore muscle function in a Duchenne muscular dystrophy mouse model. In this study, anti-RANKL therapy was evaluated in a more severe mouse model, specifically 4-week-old male dy2J/dy2J mice, which recapitulate key CMD1A features. A 1-month anti-RANKL treatment significantly improved specific muscle strength, increased myofiber cross-sectional area, and reduced edema and immune cell infiltration. It also enhanced bone strength and microarchitecture. However, absolute muscle force and global motor performance remained unchanged. Overall, anti-RANKL treatment improved muscle intrinsic properties and bone parameters in dy2J/dy2J dystrophic mice, but these improvements were insufficient to enhance absolute muscle force or global motor performance.