Lamin A/C depletion from myofibers and satellite cells in mice reveals selective muscle pathology

Abstract

Mutations in the laminA/C gene (LMNA), which encodes the nuclear lamina proteins lamin A and lamin C (lamin A/C), have been linked to different human diseases affecting different tissues. Most LMNA mutations cause cardiomyopathy and muscular dystrophy, such as autosomal dominant Emery-Dreifuss muscular dystrophy. Recent studies to understand striated muscle laminopathies have taken advantage of Lmna conditional knockout mice to examine the effects of lamin A/C depletion in cardiomyocytes and cardiac fibroblasts. However, the role of lamin A/C in skeletal muscle has largely been uncharacterized using conditional knockout mice. We used different mouse lines to deplete lamin A/C from specific cell types in striated muscle. Lamin A/C depletion from fetal myofibers and cardiomyocytes led to no observable phenotype in the skeletal muscles despite leading to dramatic heart dilation and early lethality. Depletion of lamin A/C from both skeletal myofibers and satellite cells was lethal, with the most dramatic myopathic abnormalities observed in the intrinsic muscles of the tongue. The presence of lamin A/C in skeletal muscle satellite cells prevented the development of lethal myopathy when the proteins were deleted only from differentiated myofibers. Overall, our results provide a foundation for understanding the roles of lamin A/C in muscle maintenance and development, including the variable skeletal muscle involvement and much more invariant cardiomyopathy in patients with LMNA mutations.