Tuning MYMK and MYMX fusogens expression to characterize their role in the pathogenesis of LAMA2-related congenital muscular dystrophy

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2025.

Mymk and Mymx are specialized proteins found in muscle cells that play a crucial role in helping muscle precursor cells, called myoblasts, fuse together to form mature muscle fibers. Normally, these proteins are only active in muscle stem cells and are turned off in adult muscle fibers. However, in certain muscle diseases, such as muscular dystrophy, these proteins were observed to be altered in muscle precursor cells and remain active in mature muscle fibers, leading to poor muscle regeneration, increased muscle damage and wasting, and cell death. These processed are also severely compromised in LAMA2-RD, a subtype of muscular dystrophy caused by a defect in a protein called laminin-211 (also known as merosin). Analysing muscle biopsies and muscle precursor cells of LAMA2-RD patients and dystrophic mice lacking merosin we confirmed that the expression of both Mymk and Mymx is altered compared to healthy controls. Our project aims therefore to explore how changing the expression of these proteins, either by increasing or decreasing their levels, will impact cell growth and survival affecting muscle formation in patient-derived cells and muscle precursor cells obtained from dystrophic mice. We will also modulate the expression of both genes in dystrophic mice lacking merosin in the attempt to ameliorate muscle regeneration and reduce muscle loss in this model. Our research could therefore reveal important new insights into the molecular events driving muscle fiber formation in dystrophic contexts and potentially lead to new strategies for treating these conditions and improving patient health.