Background: 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.
Aims: 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: Bile-duct ligated (BDL) rats were divided into 4 experimental groups; 1) Sham; 2) BDL; 3) Sham + OP; 4) BDL + OP. OP was administered orally by gavage (1g/kg) daily for 5 weeks starting 1 week after surgery. Two days before sacrifice, locomotor activity (day/night) was assessed in infrared beam cages for 24 h. The day of the sacrifice, body weight, fat and lean mass (EchoMRI) were measured, followed by i.p. injection of a stable isotopes tracers cocktail (Phe/Gly) in order to asses fractional synthesis of protein (FSR). At sacrifice, samples were collected to measure blood ammonia (commercial kit), cerebral edema (specific gravity method) and muscle FSR.
Results : At 6-weeks, 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. Body weight decreased in BDL rats compared to sham-operated controls (360.2g±13.6 vs 476.8g±10.4; p<0.001) and significantly increased following OP-treatment (429.6g±117.9; p<0.001 vs BDL). This was due to a higher gain of lean mass in OP-treated BDL rats compared to BDL rats (303.1g±10.7 in BDL+OP vs 264.4g±10.5 in BDL, p<0.01). This was accompanied by increased muscle FSR in OP-treated BDL rats. Fat mass remained unchanged between treated and untreated BDL groups. OP treatment also normalized brain water content 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. Moreover, OP long-term treatment is a safe, non-antibiotic alternative with protective effects on the development of cirrhosis complications such as HE 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.