CIRBP maintains skeletal muscle mitochondrial energy homeostasis via mt-ATP6 to ameliorate sarcopenia.

Sarcopenia, characterized by progressive loss of skeletal muscle mass and function, represents a major public health challenge in aging societies; its underlying molecular mechanisms remain incompletely understood, and no approved disease-specific pharmacotherapy exists. Here, we demonstrate that CIRBP is essential for skeletal muscle homeostatic maintenance during aging. Eighteen-month-old Cirbp^-/- mice exhibited a canonical sarcopenic phenotype-reduced compound muscle action potential amplitude, decreased grip strength, accelerated fatigue, and prominent myofiber atrophy-accompanied by coordinate upregulation of the ubiquitin-proteasome effectors Atrogin-1, MuRF1, and Myostatin. Whole-transcriptome RNA sequencing identified 814 differentially expressed genes, predominantly downregulated, among which mt-Atp6-encoding mitochondrial ATP synthase subunit 6-exhibited the most pronounced reduction in absolute expression. CIRBP deficiency led to coordinate downregulation of Atp6 mRNA and ATP6 protein, accompanied by severe mitochondrial cristae disruption and oxidative phosphorylation dysfunction, collectively producing chronic energy insufficiency that drove protein degradation pathway activation and progressive myofiber atrophy. Conversely, AAV-mediated CIRBP overexpression simultaneously upregulated ATP6 expression, suppressed protein degradation pathway activation, and substantially improved skeletal muscle function in aged mice at both electrophysiological and mechanical levels. This study establishes the CIRBP-Atp6 mRNA-mitochondrial energy metabolism regulatory axis as a central node in skeletal muscle aging homeostasis, providing a new mechanistic framework and potential therapeutic targets for sarcopenia intervention.