Sarcopenia or skeletal muscle loss is a frequent, potentially reversible complication in
cirrhosis that adversely affects clinical outcomes.
Hyperammonemia is a consistent abnormality in
cirrhosis that results in impaired skeletal muscle
protein synthesis and breakdown (proteostasis). Despite the availability of effective
ammonia-lowering
therapies, whether lowering
ammonia restores proteostasis and increases muscle mass is unknown. Myotube diameter,
protein synthesis, and molecular responses in C2C12 murine myotubes to withdrawal of
ammonium acetate following 24-hour exposure to 10 mM
ammonium acetate were complemented by in vivo studies in the hyperammonemic
portacaval anastomosis rat and
sham-operated, pair-fed Sprague-Dawley rats treated with
ammonia-lowering
therapy by
l-ornithine l-aspartate and
rifaximin orally for 4 weeks. We observed reduced myotube diameter, impaired
protein synthesis, and increased autophagy flux in response to
hyperammonemia, which were partially reversed following 24-hour and 48-hour withdrawal of
ammonium acetate. Consistently, 4 weeks of
ammonia-lowering
therapy resulted in significant lowering of blood and skeletal muscle
ammonia, increase in lean body mass, improved grip strength, higher skeletal muscle mass and diameter, and an increase in type 2 fibers in treated compared to untreated
portacaval anastomosis rats. The increased skeletal muscle
myostatin expression, reduced
mammalian target of rapamycin complex 1 function, and hyperammonemic stress response including autophagy markers normally found in
portacaval anastomosis rats were reversed by treatment with
ammonia-lowering
therapy. Despite significant improvement, molecular and functional readouts were not completely reversed by
ammonia-lowering measures.
CONCLUSION: