The Conjugated Bile Acids Profile Suggests a Novel Liver‐Muscle Axis Associated With Sarcopenia in Chronic Liver Disease

TL;DR

This study shows that elevated bile acids from the liver are linked to muscle loss in chronic liver disease, suggesting a new target for treatment.

Contribution

The study identifies conjugated bile acids as a novel liver-derived factor contributing to sarcopenia in chronic liver disease.

Findings

Elevated conjugated bile acids correlate with reduced muscle mass and inflammation in CLD patients.

Muscle biopsies show a shift toward slow-twitch fibers and reduced fast-twitch fibers linked to bile acid levels.

In vitro experiments confirm that bile acids alter muscle cell markers, supporting their role in muscle pathology.

Abstract

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.

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.

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 cm2) compared to controls (39.78 ± 4.38 cm2, 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.

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.

Elevated conjugated bile acids (C‐BAs) are suggested to be a liver‐derived humoral factor that is associated with reduced muscle mass and muscle pathology in human chronic liver disease (CLD).C‐BAs elevation is associated with detrimental molecular and phenotypic reprogramming of muscle.C‐BAs may represent an actionable therapeutic target. Modulating BA profiles could offer a strategy for risk stratification and for mitigating muscle catabolism in vulnerable CLD patients.

Elevated conjugated bile acids (C‐BAs) are suggested to be a liver‐derived humoral factor that is associated with reduced muscle mass and muscle pathology in human chronic liver disease (CLD).

C‐BAs elevation is associated with detrimental molecular and phenotypic reprogramming of muscle.

C‐BAs may represent an actionable therapeutic target. Modulating BA profiles could offer a strategy for risk stratification and for mitigating muscle catabolism in vulnerable CLD patients.

Figures