Vemurafenib improves muscle histopathology in a mouse model of LAMA2-related congenital muscular dystrophy

Laminin-alpha 2-related congenital muscular dystrophy (LAMA2-CMD) is a neuromuscular disease affecting around 1-9 in 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-alpha 2 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. As vemurafenib is aUSFood and Drug Administration (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 dy(W-/-) mouse model of LAMA2-CMD. Our results show that vemurafenib reduced muscle fibrosis, increased myofiber size and reduced the percentage of fibers with centrally located nuclei in dy(W-/-) mouse hindlimbs. These studies show that treatment with vemurafenib restored the TGF-beta/SMAD3 andmTORC1/p70S6K signaling pathways in skeletal muscle. Together, our results indicate that vemurafenib partially improves histopathology but does not improve muscle function in a mouse model of LAMA2-CMD.

Automated summary

LAMA2-CMD is a neuromuscular disease caused by mutations in the LAMA2 gene, leading to the loss of laminin-211/221 heterotrimers in skeletal muscle. Patients exhibit severe hypotonia and progressive muscle weakness, with no effective treatment currently available. The loss of laminin-alpha 2 results in muscle degeneration, defective muscle repair, and dysregulation of multiple signaling pathways. Vemurafenib, a serine/threonine kinase inhibitor, was found to partially restore signaling pathways and improve histopathology in a mouse model of LAMA2-CMD, but did not improve muscle function.