Resistance training prevents the development of sarcopenia induced by chronic cholestatic liver disease

Abstract

Sarcopenia secondary to chronic cholestatic liver disease (CCLD) is linked to activation of the ubiquitin-proteasome system (UPS) and autophagy-lysosome system (ALS), impaired mitochondrial dynamics, and diminished mTOR signaling. Resistance training (RT) has shown benefits against age-related sarcopenia, but its effects on CCLD-associated sarcopenia have not been explored. This study investigated the effects of RT in a mouse model of CCLD-induced sarcopenia. Male C57BL/6J mice developed CCLD-induced sarcopenia via a six-week diet containing the hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine while performing RT. Assessments included muscle strength, mass, physical performance, fiber diameter, cross-sectional area (CSA), ultrastructure, mitochondrial morphology, dynamics, respiratory function, ALS and UPS markers at the transcriptional and protein levels, and mTOR phosphorylation. RT markedly enhanced muscle strength, mass, and performance in CCLD mice. It maintained muscle fiber diameter and CSA, prevented loss of sarcomere proteins, and improved ultrastructure. RT preserved mitochondrial density, dynamics (DRP-1, mitofusin-2, OPA-1), PGC-1α levels, and oxygen consumption, normalized MuRF-1 and atrogin-1 expression, prevented transcriptional and protein induction of autophagy markers (LC3B, p62), and restored mTOR phosphorylation. These results demonstrate that RT prevents CCLD-related sarcopenia by inhibiting proteolytic systems and reactivating anabolic and mitochondrial pathways, offering a promising non-drug approach to protect skeletal muscle in this condition.