Ammonia lowering reverses sarcopenia of cirrhosis by restoring skeletal muscle proteostasis

Abstract

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 availability of effective ammonia lowering therapies, whether lowering ammonia restores proteostasis and reverses muscle mass is unknown. Myotube diameter, protein synthesis and molecular responses in C2C12 murine myotubes to withdrawal of ammonium acetate following 24 h exposure to 10mM ammonium acetate were complemented by in vivo studies in the hyperammonemic portacaval anastomosis rat (PCA) and sham operated, pair-fed (SO) 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 that were partially reversed following 24h and 48h 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 and higher skeletal muscle mass, diameter and an increase in type II fibers in the treated compared to untreated PCA rats. Increased skeletal muscle myostatin expression, reduced mTORC1 function, and the hyperammonemic stress response including autophagy markers were also reversed in the PCA rats treated with ammonia lowering therapy. Despite significant improvement, molecular and functional readouts were not completely reversed by ammonia lowering measures. Conclusions Ammonia lowering therapy results in improvement in skeletal muscle phenotype, function and molecular perturbations of hyperammonemia. These preclinical studies complement previous studies on ammonia induced skeletal muscle loss and lay the foundation for prolonged ammonia lowering therapy to reverse sarcopenia of cirrhosis.

Hepatic encephalopathy impacts the predictive value of the Fried Frailty Index

“…These include improvements after HE-therapy of poor patient reported outcomes, 20 coordination (in a driving simulator), 21 and, although it has been studied only in preclinical models, ammonia lowering therapy may reverse ammonia-induced sarcopenia. 14 Additionally, At a minimum, owing to the adverse impact of sarcopenia on frailty and waitlist mortality and the salutary effect of improved nutrition on HE, protein intake should be increased in patients with HE to 1.25 g/kg ideal bodyweight. 22 Further study of the role of screening tests for subclinical HE on longitudinal assessments of frailty, potentially by using point-of-care tests such as the EncephalApp Stroop, 23,24 are warranted.…”

“…HE is caused in part by hyperammonemia, a potent driver of muscle catabolism which leads to weakness and sarcopenia. 13,14 Further, the symptoms of HE exacerbate frailty: anorexia compounds malnutrition and sarcopenia, 15 poor coordination leads to falls, and hospitalization for HE worsens physical decline. Despite a plausible relationship between HE and frailty, data are limited regarding how HE impacts both the frailty phenotype and the outcomes reported to be associated with frailty.…”

Exercise and physical activity for patients with end‐stage liver disease: Improving functional status and sarcopenia while on the transplant waiting list

“…A study with in vitro and in vivo data suggests that NH 3 ‐lowering treatment with L‐ornithine‐L‐aspartate restores net protein balance, which could directly impact muscle mass in patients . This agent is not available in the United States, and although a newer compound recently tested in a phase 2 clinical trial, ornithine phenylacetate, could potentially decrease hyperammonemia, it is unknown whether the concomitant urinary loss of phenylacetylglutamine would have a negative nutritional impact.…”

Hepatoprotection by L-Ornithine L-Aspartate in Non-Alcoholic Fatty Liver Disease

“…Mechanisms relating sarcopenia to NAFLD include proinflammatory factors with the potential to result in liver injury [9]. It has been reported that LOLA treatment in patients with cirrhosis [10,11] or experimental animals with chronic liver failure [12] results in the restoration of muscle proteostasis and significant improvements of muscle function. It is possible that the apparent hepatoprotective properties of LOLA in patients with NAFLD are mediated, at least in part, via mechanisms involving improvements of skeletal muscle function.…”