In:
Frontiers in Physiology, Frontiers Media SA, Vol. 13 ( 2022-11-1)
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1664-042X
DOI:
10.3389/fphys.2022.993995
DOI:
10.3389/fphys.2022.993995.s001
DOI:
10.3389/fphys.2022.993995.s002
DOI:
10.3389/fphys.2022.993995.s003
DOI:
10.3389/fphys.2022.993995.s004
Language:
Unknown
Publisher:
Frontiers Media SA
Publication Date:
2022
detail.hit.zdb_id:
2564217-0
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