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

Abstract

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.

Muscle eosinophilia is a hallmark of chronic disease in facioscapulohumeral muscular dystrophy

“…Interestingly, muscle eosinophilia without blood eosinophilia seems to be rather common in muscular dystrophies. For example, muscle eosinophilia in the dyW mouse model of LAMA2 -CMD [ 57 ] correlates with increased eotaxin expression in the skeletal muscle in dyW mice [ 57 , 67 , 68 ], although eotaxin levels in the serum of dyW mice are normal [ 67 ]. Proteomic analysis of human muscle biopsies also revealed a significant increase in eotaxin expression in LAMA2 -CMD patients [ 67 ].…”

Merosin-deficient congenital muscular dystrophy type 1a: detection of LAMA2 variants in Vietnamese patients

“…N-acetyl-L-cysteine treatment preserved muscle strength, reduced fibrosis, central nucleation, apoptosis, inflammation and oxidative stress, and vitamin E treatment improved skeletal muscle morphological features, reduced inflammation and reactive oxygen species levels in dy 2J / dy 2J mice ( Harandi et al, 2020 ). Vemurafenib treatment improved muscle histopathology and restored the TGF-β/SMAD3 and mTORC1/p70S6K signaling pathways in mouse models, but did not restore the myomatrix ( Oliveira-Santos et al, 2023 ). However, vemurafenib treatment might be combined with other therapies that restore the myomatrix.…”

Pharmacotherapeutic Approaches to Treatment of Muscular Dystrophies

“…Though there is considerable preclinical interest in losartan as an anti-fibrotic agent, there are no ongoing trials for its use in MDC1A. The FDA-approved serine/threonine kinase inhibitor vemurafenib effectively ameliorates fibrosis in dy 3K /dy 3K mice [229]. Treatment resulted in a reduction in TGF-β and mTORC1/p70S6K signaling.…”