Hepatic senescence triggered by statins decreases systemic IGF-1 signaling to drive skeletal muscle atrophy

Statins lower circulating cholesterol by inhibiting hepatic 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). However, their clinical use is frequently limited by statin-associated muscle complications, the underlying mechanisms of which remain incompletely understood. Here we demonstrate that lovastatin and atorvastatin induce cellular senescence in hepatocytes and hepatic tissue, as evidenced by increased senescence-associated β-galactosidase (SA-β-gal) activity and induction of the canonical markers p21 and p16. Among senescence-associated secretory phenotype (SASP), insulin-like growth factor-1 (IGF-1) was selectively and significantly reduced. In a transwell coculture system, senescent AML12 hepatocytes impaired C2C12 myogenesis, decreased myotube diameter, and upregulated the muscle atrophy markers Atrogin-1 and MuRF1. Consistent with these in vitro findings, in vivo lovastatin and ezetimibe (LE) exposure increased hepatic SA-β-gal-positive area, elevated p21/p16 expression, and lowered circulating IGF-1. Tibialis anterior muscle displayed reduced fiber cross-sectional area with a smaller-shifted size distribution, heightened atrophy signaling, and diminished AKT/mTOR pathway activation. Together, these findings support a liver-to-muscle endocrine axis in which lovastatin-induced hepatic senescence suppresses IGF-1, secondarily impairing myogenesis and promoting skeletal muscle atrophy via attenuation of AKT/mTOR signaling. Targeting hepatic senescence or restoring IGF-1/AKT/mTOR activity may offer therapeutic strategies to mitigate statin-associated myopathy.