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).