ARIIZUMI Shunichi    Department   School of Medicine(Tokyo Women's Medical University Hospital), School of Medicine    Position   Associate Professor
Article types	Original article
Language	English
Peer review	Non peer reviewed
Title	p62/Sqstm1 rescue in muscle retards the progression of steatohepatitis in p62/Sqstm1-null mice fed a high-fat diet
Journal	Formal name：Frontiers in physiology Abbreviation：Front Physiol ISSN code：1664042X/1664042X
Domestic / Foregin	Foregin
Volume, Issue, Page	13,pp.993995
Author and coauthor	Miura Ikuru, Okada Kosuke, Ishii Akiko, Warabi Eiji, Watahiki Takahisa, To Keii, Shimano Hitoshi, Ariizumi Shunichi, Shoda Junichi
Publication date	2022/11
Summary	Introduction: Obesity is a risk factor for many diseases because it leads to a reduction in skeletal muscle mass and promotes insulin resistance. p62/Sqstm1-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. Methods: We generated muscle-specific p62 gene rescue mice (p62-mRes), which express p62 only in muscle and were derived from p62-knock out mice (p62 KIKI ) using the cre/loxp system. p62 KIKI and p62-mRes mice were fed an HFD for 20 weeks and their phenotypes were compared. Results: HFD-feeding caused severe obesity in both p62 KIKI and p62-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 p62-mRes mice than in p62 KIKI . The glucose tolerance and insulin sensitivity of the p62-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 p62-mRes mice. p62 KIKI mice developed severe NASH when fed an HFD, but the progression of NASH was retarded by p62 gene rescue in muscle, and the expression of Tgf-β1, which encodes a factor that promotes hepatic fibrosis, was reduced. Conclusion: Rescue of muscle-specific p62 in the whole-body p62 knock-out mice ameliorates the insulin resistance and retards the progression of NASH caused by systemic p62 ablation.
DOI	10.3389/fphys.2022.993995
PMID	36439272