A Mechanistic basis of fast myofiber vulnerability in neuromuscular diseases [Multiome]

Skeletal muscle denervation is a characteristic feature of neuromuscular diseases such as amyotrophic lateral sclerosis (ALS) and sarcopenia, leading to atrophy, loss of muscle strength, and poor patient outcomes. Myofibers are typically classified into slow oxidative and fast glycolytic types based on their contractile and metabolic properties. Neuromuscular diseases predominantly affect fast myofibers, while slow myofibers are relatively spared. However, the mechanisms underlying the heightened susceptibility of fast myofibers to disease and atrophy remain unclear. To investigate this, we analyzed the transcriptional profiles of innervated and denervated myonuclei. Our findings revealed that the fast muscle gene program and the transcription factor Maf are repressed during denervation. Notably, overexpression of Maf in the skeletal muscles of mice prevented loss of muscle mass and myofiber atrophy caused by denervation. Single-nucleus RNA sequencing and ATAC sequencing demonstrated that Maf overexpression reprogrammed denervated myonuclei by repressing atrophic gene programs and reactivating fast muscle gene expression. Similar repression of fast muscle genes and Maf was observed in muscles from mice and humans with ALS. Consistent with these findings, Maf overexpression in human skeletal muscle cells induced the expression of fast muscle genes while suppressing atrophic gene expression. Our findings highlight a key role for Maf in maintaining muscle mass and demonstrate that its repression contributes to the progression of neuromuscular diseases in both mice and humans. Modulating Maf activity could offer a promising therapeutic strategy to preserve skeletal muscle function during disease, aging, or injury.