TRalpha Deficiency Drives Sarcopenia by Disrupting Perimitochondrial Targeting of Pink1 mRNA and Mitophagy
Skeletal muscle-specific ablation of thyroid hormone receptor alpha (TRalpha) in young mice is sufficient to recapitulate key phenotypic hallmarks of age-related sarcopenia--including myofiber atrophy, exercise intolerance, and mitochondrial quality control failure--establishing receptor decline as a cell-autonomous driver of sarcopenia pathogenesis rather than a passive biomarker. The underlying mechanism reveals how systemic endocrine signals culminate in organelle-specific quality control defects: TRalpha transcriptionally drives the RNA-binding protein CLUH, which facilitates the perimitochondrial enrichment of Pink1 mRNA for localized synthesis of the mitophagy-initiating kinase. Consequently, TRalpha loss disrupts perimitochondrial Pink1 mRNA localization, impairing local PINK1 abundance and mitophagic priming, leading to accumulation of damaged mitochondria. Restoring CLUH expression rescues Pink1 mRNA spatial localization, mitophagy flux, and cellular senescence markers in both TRalpha-deficient myofibers and naturally aged muscle cells. These findings identify spatial transcriptome organization as an underappreciated regulatory layer in muscle wasting and provide a genetically defined framework linking endocrine decline to organelle-level post-transcriptional regulation.