Cause and management of muscle wasting in chronic liver disease

Abstract

Purpose of review: Sarcopenia or loss of skeletal muscle mass is the major component of malnutrition and occurs in the majority of patients with liver disease. Lower muscle contractile function also contributes to the adverse consequences of sarcopenia. There are no effective therapies to prevent or reverse sarcopenia in liver disease. This review will discuss the advances in diagnosis, pathogenesis, and treatment options for sarcopenia in liver disease.

Recent findings: Sarcopenia increases mortality and risk of development of other complications of cirrhosis, and worsens postliver transplant outcomes while quality of life is decreased. Unlike other complications of cirrhosis that reverse after liver transplantation, sarcopenia may not improve and actually worsens. Impaired skeletal muscle protein synthesis and increased proteolysis via autophagy contribute to sarcopenia. Hyperammonemia is the best-studied mediator of the liver-muscle axis. Molecular studies show increased expression of myostatin whereas metabolic studies show impaired mitochondrial function and tricarboxylic acid cycle intermediates because of cataplerosis of α-ketoglutarate. Impaired skeletal muscle pyruvate and fatty acid oxidation during hyperammonemia suggest amino acids are diverted to acetyl CoA and potentially aggravate hyperammonemia. Nutritional supplementation is of limited or no benefit and suggests that cirrhosis is a state of anabolic resistance. Exercise may be beneficial but whether it overcomes anabolic resistance is not known.

Summary: The high clinical significance of sarcopenia is well established. Current approaches to nutritional supplementation have not been effective in reversing sarcopenia because of anabolic resistance. Myostatin antagonists, specific amino acid supplementation, mitochondrial protection, and combination endurance-resistance exercise are potential future therapeutic options.

Figure 1. Overview of ammonia induced metabolic and signaling perturbations

Impaired hepatic ureagenesis results in skeletal muscle hyperammonemia. Ammonia transcriptionally upregulates myostatin via a p65NFkB mediated mechanism and decreases α ketoglutarate by cataplerosis. Reduction in α ketoglurate can stabilize hypoxia inducible factor 1α (HIF1α) that in turn can activate myostatin and inhibit pyruvate to acetyl CoA oxidation (dotted lines are preliminary studies from our laboratory).

Figure 2. Metabolic abnormalities that contribute to and potential therapeutic targets

Accelerated lipolysis generates acetyl CoA from fatty acids due to impaired pyruvate dehydrogenase (PDH) by hypoxia inducible factor 1α (HIF1α) via pyruvate dehydrogenase kinase (PDK) and possibly directly by ammonia. Cataplerosis of α-ketoglutarate (αKG) by to form glutamate is a metabolic disposal pathway activated in the muscle during hyperammonemia. Lower αKG results in stabilization of HIF1α, decreased mTORC1 activation and decreased tricarboxylic acid (TCA) cycle flux and lower ATP synthesis. These perturbations contribute to lower protein synthesis. Homeostatic responses include the utilization of branched chain amino acids to provide anaplerosis for generate αKG (isoleucine, valine) and acetyl CoA (leucine, isoleucine) with increased transport of branched chain amino acids from circulation for metabolic disposal. Ammonia via a p65NFkB mediated mechanism also activates myostatin that in turn inhibits mTORC1. These metabolic and molecular perturbations contribute to decreased sensitivity to anabolic stimuli (anabolic resistance) that can be potentially reversed by intervention at targeted sites. 1. Long term ammonia lowering strategies. 2. Myostatin blocking agent including antagomirs. 3. L-leucine provides acetyl-CoA, activates mTORC1 and protein synthesis. 4. Glucogenic amino acids can be a source of anaplerotic input to provide succinyl CoA replacing the loss of (cataplerosis) of αKG that is converted to glutamate during hyperammonemia (since skeletal muscle cannot generate urea). 5. Cell permeable esters of αKG are a potential strategy to reverse cataplerosis and a novel method to increase muscle ammonia disposal. 6. Physical activity stimulates mTORC1 via phosphatidic acid.

Figure 3. Overview of strategies to reverse sarcopenia and potentially contractile dysfunction in cirrhosis

Bold, oval encircled targets and putative interventions (italics). Liver transplantation is a definitive therapy but may not reverse sarcopenia. Hyperammonemia is the best studied mediator of the liver-muscle axis but duration of therapy needed to lower muscle ammonia is not known. It is also not known if lowering muscle ammonia will indeed reverse the metabolic and molecular perturbations in the muscle with functional translation into increased muscle mass, improved contractile function and better clinical outcomes. Starvation response has been addressed using frequent feeds, nocturnal meals and late evening snacks with protein supplementation and shown to be of some benefit. Direct myostatin antagonists are in various stages of development and preclinical rodent studies have shown benefit. Amino acid supplementation with branched chain amino acids, anaplerotic substrates including cell permeable tricarboxyclic acid intermediates are exciting novel approaches being evaluated in preclinical studies. Therapies to reverse hormone deficiencies and endotoxemia have not been effective but the impact of alterations in gut microbiome has not been evaluated and may be another potential therapeutic target.