Cholanemia Induces Skeletal Muscle Wasting Despite Stimulation of Translation Initiation, Decreased Autophagy, Activation of Yes Associated Protein (yap) and Proteosomal Signal Activation in Mice

Skeletal muscle wasting is a common co‐morbidity in cholestatic liver diseases. We hypothesize that cholestasis and bile acid (BA) excess (cholanemia) directly induces muscle atrophy by decreasing translation and stimulating protein degradation in muscle. Biliary fibrosis and cholestasis was induced in 6–8 week old male C57BL/6J mice by feeding a DDC supplemented diet for 3 weeks and compared with isocaloric chow fed mice (n=3/group). DEXA scan, exercise tolerance, and fasting circulating BA, glucose and insulin were analyzed, and quadricep muscle signaling was determined. Compared to controls, DDC had 1/3 less food intake, lower body weight (17±0.6 vs. 25±0.5g), lean (11.4±0.8 vs. 16.1±0.4g) and fat mass (2.3±0.1 vs. 3±0.2g) and demonstrated early fatigue on the treadmill. DDC had liver injury, cholestasis, cholanemia (BA: 1000±250 vs. 7±1 μmol/L), and lower glucose (60±5 vs. 150±15mg/dl) and insulin levels (0.15±0.01 vs. 0.53±0.01 ng/L) than controls. DDC had lower muscle mass (0.05±0.006 vs. 0.14±0.01g), higher phosphorylation of AKT, 4E‐BP1 and eIF4G, lower AMPK, eIF2α, YAP phosphorylation, and lower LC3‐II and MuRF1 abundance than controls. These findings suggest that cholanemia stimulates translation initiation, and represses autophagy and protein degradation signaling despite physical evidence of muscle atrophy. (Supported by Pediatric Critical Care Internal Funding)