Background and Aims: Chronic liver disease (CLD) induces numerous complications including muscle mass loss and hepatic encephalopathy (HE) which negatively impact the clinical outcome. Furthermore, muscle mass wasting and HE have been shown to lead to poor prognosis following liver transplantation. Hyperammonemia is considered the central component in the pathogenesis of HE, however recent studies have suggested ammonia to be toxic to other organs besides the brain, such as the muscle. The aim of this study was to investigate the effect of ammonia on muscle mass in rats treated with an oral formulation of ornithine phenylacetate (OP; OCR-002).
Methods: Six-week bile-duct ligated (BDL) and sham rats were used. OP was administered orally by gavage (1g/kg) daily for 5 weeks starting 1 week after surgery. Locomotor activity (day/night) was assessed in infrared beam cages for 24 h. Body weight, fat and lean mass (EchoMRI) were measured, followed by i.p. injection of a stable isotopes tracers cocktail in order to asses fractional synthesis of protein (FSR). Samples for blood ammonia, cerebral edema and muscle FSR were collected.
Results: BDL rats demonstrated a 4-fold increase in blood ammonia vs sham-operated controls. This increase was reduced by 40% in OP-treated BDL rats. BDL rats gained less body weight compared to sham-operated controls (body weight of 360.2g ± 13.6 vs 476.8g ± 10.38 p<0.001) which was accompanied with a lower gain of lean mass and a lower muscle FSR. OP-treated BDL rats showed a significant increase in body weight (429.6g ± 117.9 p<0.001 vs BDL) with a significant higher lean mass (303.1g ± 10.7 in BDL+OP vs 264.4g ± 10.5 in BDL p<0.01). Fat mass remained unchanged between the treated and untreated BDL groups. OP treatment normalized brain water content in BDL rats. In contrast, OP-treatment reduced muscle FSR in SHAM animals, but not in BDL rats. Locomotor activity in BDL rats was reduced compared with sham-operated controls but no significant change was found between BDL+OP and SHAM+OP.
Conclusions: This is the first study demonstrating the efficient ammonia-lowering effect of an oral formulation of OP. Long-term treatment with OP is a safe, non-antibiotic alternative demonstrating a significant ammonia-lowering effect, as well as a protective effect on the development of brain edema and muscle mass loss in rats with CLD. Whether the effect of OP on muscle mass loss attenuation is a result of lowering blood ammonia or directly improves muscle metabolism remains to be established.