LMNA-related muscular dystrophy involving myoblast proliferation and apoptosis through the FOXO1/GADD45A pathway

LMNA-related muscular dystrophy is a major disease phenotype causing mortality and morbidity in laminopathies, but its pathogenesis is still unclear. To explore the molecular pathogenesis, a knock-in mouse harbouring the Lmna-W520R mutation was modelled. Morphological and motor functional analyses showed that homozygous mutant mice revealed severe muscular atrophy, profound motor dysfunction, and shortened lifespan, while heterozygotes showed a variant arrangement of muscle bundles and mildly reduced motor capacity. Mechanistically, the FOXO1/GADD45A pathway involving muscle atrophy processes was found to be altered in vitro and in vivo assays. The expression levels of FOXO1 and its downstream regulatory molecule GADD45A significantly increased in atrophic muscle tissue. The elevated expression of FOXO1 was associated with decreased H3K27me3 in its gene promotor region. Overexpression of GADD45A induced apoptosis and cell cycle arrest of myoblasts in vitro, and it could be partially restored by the FOXO1 inhibitor AS1842856, which also slowed the muscle atrophy process with improved motor function and prolonged survival time of homozygous mutant mice in vivo. Notably, the inhibitor also partly rescued the apoptosis and cell cycle arrest of hiPSC-derived myoblasts harbouring the LMNA-W520R mutation. Together, these data suggest that the activation of the FOXO1/GADD45A pathway contributes to the pathogenesis of LMNA-related muscle atrophy, and it might serve as a potential therapeutic target for laminopathies.