Vemurafenib partially ameliorates muscle histopathology but does not improve muscle function in a mouse model of LAMA2-CMD.

Laminin-α2-related Congenital Muscular Dystrophy (LAMA2-CMD) is a neuromuscular disease affecting around 1-9/1,000,000 children. LAMA2-CMD is caused by mutations in the LAMA2 gene resulting in the loss of laminin-211/221 heterotrimers in skeletal muscle. LAMA2-CMD patients exhibit severe hypotonia and progressive muscle weakness. Currently, there is no effective treatment for LAMA2-CMD and patients die prematurely. The loss of laminin-α2 results in muscle degeneration, defective muscle repair, and dysregulation of multiple signaling pathways. Signaling pathways that regulate muscle metabolism, survival, and fibrosis have been shown to be dysregulated in LAMA2-CMD. Since vemurafenib is an FDA-approved serine/threonine kinase inhibitor, we investigated whether vemurafenib could restore some of the serine/threonine kinase-related signaling pathways and prevent disease progression in the dyW-/- mouse model of LAMA2-CMD. Our results show vemurafenib reduced muscle fibrosis, increased myofiber size, and reduced the percentage of fibers with centrally located nuclei in dyW-/- mice hindlimbs. These studies show treatment with vemurafenib restored the TGF-β/SMAD3 and mTORC1/p70S6K signaling pathways in skeletal muscle. Together our results indicate vemurafenib partially improves histopathology but does not improve muscle function in a mouse model of LAMA2-CMD.