Abstract
BACKGROUND: Liver-related sarcopenia is a devastating systemic complication of chronic liver disease (CLD) driven by mechanisms extending beyond nutritional deficiency. However, the role of liver-derived humoral factors remains unclear. We utilised a unique cohort of human skeletal muscle biopsies to test the hypothesis that serum conjugated bile acids (C-BAs) act as key mediators of this liver-muscle cross-talk. METHODS: Serum and rectus abdominis muscle samples were meticulously collected from 36 CLD patients and 6 non-CLD controls during elective surgery. Multifidus-erector spinae and psoas muscle areas were quantified from CT images. Comprehensive correlations were analysed between C-BAs and molecular markers of muscle inflammation and fibre-type composition. These findings were supplemented by in vitro validation using GCDCA treatment of C2C12 myotubes. RESULTS: Serum C-BAs levels were significantly elevated in CLD patients. The liver cirrhosis (LC) group exhibited a significantly smaller multifidus-erector spinae area (32.06 ± 8.05 cm(2)) compared to controls (39.78 ± 4.38 cm(2), p = 0.019). Muscle area loss was strongly correlated with hepatic reserve deterioration (ALBI/ALB) and systemic inflammation (serum IL-6). Crucially, muscle area was negatively correlated with the ratio of tauro-C-BAs (p < 0.05). Muscle biopsies showed a molecular shift: enrichment of the slow-twitch fibre marker myosin-heavy chain 7 (MYH7, type I) and a concomitant reduction of the fast-twitch marker MYH4 (type IIb), alongside signs of local chronic inflammation (p < 0.05). The reduction in MYH4 was correlated with glyco-C-BAs, a finding replicated in GCDCA-treated C2C12 myotubes. CONCLUSIONS: Elevated C-BAs may represent a critical, liver-derived humoral factor associated with the pathological features of liver-related sarcopenia. C-BA-associated muscle mass loss and systemic inflammation are reflected at the molecular level by a shift toward a slow-twitch phenotype, accumulation of macrophages and altered energy metabolism in muscle biopsies. These findings suggest that C-BAs may serve as a potentially actionable therapeutic target for mitigating muscle catabolism and improving clinical outcomes in CLD patients.