Sarcopenia from mechanism to diagnosis and treatment in liver disease

Abstract

Sarcopenia or loss of skeletal muscle mass is the major component of malnutrition and is a frequent complication in cirrhosis that adversely affects clinical outcomes. These include survival, quality of life, development of other complications and post liver transplantation survival. Radiological image analysis is currently utilized to diagnose sarcopenia in cirrhosis. Nutrient supplementation and physical activity are used to counter sarcopenia but have not been consistently effective because the underlying molecular and metabolic abnormalities persist or are not influenced by these treatments. Even though alterations in food intake, hypermetabolism, alterations in amino acid profiles, endotoxemia, accelerated starvation and decreased mobility may all contribute to sarcopenia in cirrhosis, hyperammonemia has recently gained attention as a possible mediator of the liver-muscle axis. Increased muscle ammonia causes: cataplerosis of α-ketoglutarate, increased transport of leucine in exchange for glutamine, impaired signaling by leucine, increased expression of myostatin (a transforming growth factor beta superfamily member) and an increased phosphorylation of eukaryotic initiation factor 2α. In addition, mitochondrial dysfunction, increased reactive oxygen species that decrease protein synthesis and increased autophagy mediated proteolysis, also play a role. These molecular and metabolic alterations may contribute to the anabolic resistance and inadequate response to nutrient supplementation in cirrhosis. Central and skeletal muscle fatigue contributes to impaired exercise capacity and responses. Use of proteins with low ammoniagenic potential, leucine enriched amino acid supplementation, long-term ammonia lowering strategies and a combination of resistance and endurance exercise to increase muscle mass and function may target the molecular abnormalities in the muscle. Strategies targeting endotoxemia and the gut microbiome need further evaluation.

Keywords: Clinical outcomes; Hyperammonemia; Leucine; Myostatin; Sarcopenia; mTORC1.

Figure 1. Myostatin is transcriptionally upregulated by hyperammonemia in the skeletal muscle

Ammonia enters the skeletal muscle via the transport proteins Rh B and G. In the muscle, ammonia activates transforming growth factor β activated kinase 1 (TAK1) that activates TRAF6. Activated TRAF6 (k63 polyubiquitination) activates IK kinase (IKK) that in turn phosphorylates NFkB inhibitor protein IKB. Phospho IKB is degraded via a proteasome pathway releasing p65NFkB that enters the nucleus and transcriptionally upregulates myostatin.

Figure 2. Biochemical abnormalities in the skeletal muscle that contribute impaired protein synthesis and increased autophagy with consequent sarcopenia

Metabolic and molecular perturbations 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

Molecular targets are in bold and encircled and putative interventions are italicized.