Myogenic Effectors and Disease

Skeletal muscle is essential for life. Inside muscle fibers, filaments of actin and myosin slide on each other to generate the mechanical forces that drive muscle contraction, movement, and breathing. Mutations in muscle-related genes can cause severe diseases in humans. Here we characterize the role of three understudied muscle-specific genes and their potential contribution to human disease. We show that constitutive and juvenile loss of the nuclear envelope protein Net39 in mice recapitulates different manifestations of Emery-Dreifuss muscular dystrophy. Deletion of Net39 caused disruption of nuclear envelope integrity and associated genomic, transcriptional, and metabolic changes that compromised muscle function. Mechanistically, Net39 regulates nuclear organization by associating with LEM proteins, and gene expression by controlling the transcription factor Mef2c. In contrast, global deletion of the Kelch protein Klhl41 in mice causes severe nemaline myopathy, including neonatal lethality and aggregation of contractile proteins in muscle, particularly Nebulin. Molecularly, Klhl41 acts as a chaperone for Nebulin, and N-terminal poly-ubiquitination of Klhl41 acts as a signal to regulate its activity. Finally, we identify a novel pathogenic mutation in the cell fusogen Myomixer. We show that patients with Carey-Fineman-Ziter syndrome lose a region of Myomixer required to destabilize opposing cell membranes during myoblast fusion. Overall, our findings here highlight the contribution of understudied genes to muscle biology and the molecular etiology of muscle disorders.