PRR14 mediates mechanotransduction and regulates myofiber identity via MEF2C in skeletal muscle

Sarcopenia, characterized by the loss of muscle mass, strength, and function, predisposes adverse outcomes and its mechanism is waiting to reveal. Here, we report decrease of PRR14, a nuclear protein, in skeletal muscle results in sarcopenia. Genetically, genome-wide association studies (GWAS) identified multiple single nucleotide polymorphisms (SNPs) in PRR14 locus associated with body mass index (BMI) and total body lean mass, which indicated its association with sarcopenia; Specific knockout of skeletal muscle Prr14 in mice confirmed the causal effect; Biochemical analysis and high-throughput sequencing, including both transcriptome and approaches for the study of the epigenome (CUT&Tag sequencing and ATAC sequencing), revealed that Prr14 was required for myofiber homeostasis in skeletal muscle: Prr14 loss altered chromatin structure and reduced Mef2c activity, which in combination resulted in failure of maintaining myofiber identity and therefore sarcopenia. Our findings demonstrate that PRR14 orchestrates critical epigenetic changes and transcription factor activity to maintain myofiber identity, thereby providing novel therapeutic avenues for skeletal muscle pathologies associated with dysregulation of these mechanisms.