p62/Sqstm1 rescue in muscle retards the progression of steatohepatitis in -null mice fed a high-fat diet.

Obesity is a risk factor for many diseases because it leads to a reduction in skeletal muscle mass and promotes insulin resistance. -knockout mice are a model of metabolic syndrome; show obesity, insulin resistance, and non-alcoholic fatty liver (NAFL); and develop non-alcoholic steatohepatitis (NASH) in response to the feeding of a high-fat diet (HFD). These phenotypes suggest that muscle p62 may prevent obesity-induced muscle dysfunction. In the present study, we aimed to determine the effects of muscle p62 on skeletal muscle mass, muscle strength, insulin resistance, and NASH pathology. We generated muscle-specific gene rescue mice (-mRes), which express p62 only in muscle and were derived from -knock out mice ( ) using the system. and -mRes mice were fed an HFD for 20 weeks and their phenotypes were compared. HFD-feeding caused severe obesity in both and -mRes mice, but there was no effect of muscle p62 on body mass. Limb skeletal muscle mass, grip strength, and the cross-sectional area of muscle fibers were higher in -mRes mice than in . The glucose tolerance and insulin sensitivity of the -mRes mice were also superior. The protein expression of mechanistic target of rapamycin, which promotes muscle protein synthesis, and GLUT4, a glucose transporter in skeletal muscle, were higher in the -mRes mice. mice developed severe NASH when fed an HFD, but the progression of NASH was retarded by gene rescue in muscle, and the expression of , which encodes a factor that promotes hepatic fibrosis, was reduced. Rescue of muscle-specific in the whole-body knock-out mice ameliorates the insulin resistance and retards the progression of NASH caused by systemic ablation.