Hepatic Yap1 activates systemic catabolism and muscle loss during organ repair: evidence for a liver-derived common mechanism with cancer cachexia.

Abstract

Recovery from critical injury concomitant with restoration of functional organ mass invokes a systemic catabolic response leading to muscle and fat loss, known as cachexia. We interrogated this process using mouse models of organ repair, including liver regeneration after hepatectomy, Yap1-mediated hepatomegaly, and pneumonectomy. Both hepatectomy and Yap1 induced systemic catabolism. Muscle and adipose wasting scaled with degree of liver growth, with 10-25% reduction of muscle mass and 50-80% of fat mass. In contrast, non-regenerative lung injury did not induce tissue wasting. Liver growth elevated resting energy expenditure. Tracer studies demonstrated redistribution of muscle-derived cholesterol and amino acids to regenerating liver. Gene expression changes in livers and muscles showed high concordance between the liver growth models and cancer cachexia models, including pancreatic adenocarcinoma cachexia. We propose that cachexia is a normal and essential reparative process in organ repair and regeneration and further, that cancer cachexia is a pathological exacerbation of an adaptive process mediated by activation of Yap1 in the liver.