Attenuating hyperammonemia preserves protein synthesis and muscle mass via restoration of perturbed metabolic pathways in bile duct-ligated rats

Abstract

Sarcopenia and hepatic encephalopathy (HE) are complications of chronic liver disease (CLD), which negatively impact clinical outcomes. Hyperammonemia is considered to be the central component in the pathogenesis of HE, however ammonia's toxic effects have also been shown to impinge on extracerebral organs including the muscle. Our aim was to investigate the effect of attenuating hyperammonemia with ornithine phenylacetate (OP) on muscle mass loss and associated molecular mechanisms in rats with CLD. Six-week bile duct-ligated (BDL) rats and Sham-operated controls were treated with OP (1 g/kg, oral) for 5 weeks. Body composition, assessed by EchoMRI, and muscle protein fractional synthesis rate were evaluated. Signalling mechanisms regulating protein homeostasis, ATP content and metabolic intermediates in the tricarboxylic acid cycle (TCA) in skeletal muscle were quantified. OP treatment attenuated hyperammonemia, prevented brain edema and improved locomotor activity in BDL rats. Increased muscle ammonia, reduction in lean body mass, decreased muscle protein synthesis rate and ATP content were restored in OP-treated versus saline-treated BDL rats. TCA cycle intermediary metabolite, α-ketoglutarate, alterations of molecular markers regulating protein homeostasis including mTOR signalling and autophagy, were also preserved in muscle of OP-treated BDL rats. OP attenuated hyperammonemia, preserved muscle protein synthesis and prevented muscle mass loss in a preclinical model of CLD through restoration of perturbed signalling responses and altered TCA intermediary metabolites. Ammonia-lowering strategies have the potential for rapid clinical translation for simultaneous neuroprotection and sarcopenia prevention in patients with CLD.