Imeglimin provides dual hepatic and skeletal muscle protection in experimental MASH-associated sarcopenia.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) is frequently complicated by sarcopenia, in which mitochondrial dysfunction and inflammatory catabolic signaling are implicated. We investigated whether imeglimin, an antidiabetic mitochondrial modulator, attenuates MASH-associated muscle atrophy. METHODS: MASH-associated sarcopenia was induced in mice using a choline-deficient, L-amino acid-defined high-fat diet. After 6 weeks of feeding, imeglimin (200 mg/kg, twice daily) was administered for 6 weeks. Four groups of 10 mice were examined. Muscle phenotype, mitochondrial function, and molecular signaling were assessed. Direct effects were examined in interleukin-6 (IL-6)-stimulated C2C12 myotubes. RESULTS: Imeglimin ameliorated steatohepatitis and restored hepatic and circulating insulin-like growth factor-1 without altering food intake or fasting glucose and insulin levels. Hepatic inflammation, oxidative stress, and fibrosis were also reduced. It preserved muscle mass, grip strength, and fiber diameter; suppressed Fbxo32, Trim63, and Mstn expression; reduced FOXO3a nuclear localization; and reactivated AKT-mTOR signaling. Imeglimin restored mitochondrial biogenesis, complex I/IV activities, NAMPT expression, and intramuscular NAD+ levels while reducing inflammation and oxidative stress. It also increased the LC3-II/LC3-I ratio and reduced p62 accumulation, supporting improvement of autophagy-lysosome homeostasis. In IL-6-stimulated C2C12 myotubes, imeglimin restored myotube diameter, mitochondrial membrane potential, biogenesis, respiratory function, complex I and IV activities, and autophagy-lysosome homeostasis while suppressing atrogene induction. CONCLUSIONS: Imeglimin attenuated experimental MASH-associated muscle atrophy through coordinated improvement of hepatic function, mitochondrial homeostasis, anabolic signaling, and proteostasis without detectable changes in fasting glucose or insulin levels. These findings support further evaluation of imeglimin as a potential therapy for MASH-associated sarcopenia.