Abstract
LMNA gene encodes lamins A and C, two major components of the nuclear lamina, a network of intermediate filaments underlying the inner nuclear membrane. Most of LMNA mutations are associated with cardiac and/or skeletal muscles defects. Muscle laminopathies include Emery-Dreifuss Muscular Dystrophy, Limb-Girdle Muscular Dystrophy 1B, LMNA-related Congenital Muscular Dystrophy and Dilated Cardiomyopathy with conduction defects. To identify potential alterations in signaling pathways regulating muscle differentiation in LMNA-mutated myoblasts, we used a previously described model of conditionally immortalized murine myoblasts: H-2K cell lines. Comparing gene expression profiles in wild-type and Lmna(∆8-11) H-2K myoblasts, we identified two major alterations in the BMP (Bone Morphogenetic Protein) pathway: Bmp4 downregulation and Smad6 overexpression. We demonstrated that these impairments lead to Lmna(∆8-11) myoblasts premature differentiation and can be rescued by downregulating Smad6 expression. Finally, we showed that BMP4 pathway defects are also present in myoblasts from human patients carrying different heterozygous LMNA mutations.