PAC1 Deficiency Protects Obese Male Mice From Immobilization-Induced Muscle Atrophy by Suppressing FoxO-Atrogene Axis.

Autor:	Li Q; Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Ishikawa 920-8640, Japan., Ishii KA; Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Ishikawa 920-8640, Japan.; Department of Musculoskeletal Disease, National Center for Geriatrics and Gerontology (NCGG), Aichi 474-8511, Japan., Kamoshita K; Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Ishikawa 920-8640, Japan., Takahashi K; Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Ishikawa 920-8640, Japan., Abuduwaili H; Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Ishikawa 920-8640, Japan., Takayama H; Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Ishikawa 920-8640, Japan.; Life of Sciences Division, Engineering and Technology Department, Kanazawa University, Ishikawa 920-1192, Japan., Galicia-Medina CM; Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Ishikawa 920-8640, Japan., Tanida R; Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Ishikawa 920-8640, Japan., Ko Oo H; Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Ishikawa 920-8640, Japan., Gafiyatullina G; Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Ishikawa 920-8640, Japan., Yao X; Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Ishikawa 920-8640, Japan., Abuduyimiti T; Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Ishikawa 920-8640, Japan., Hamazaki J; Faculty of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan., Goto H; Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Ishikawa 920-8640, Japan., Nakano Y; Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Ishikawa 920-8640, Japan., Takeshita Y; Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Ishikawa 920-8640, Japan., Harada K; Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Ishikawa 920-8640, Japan., Murata S; Faculty of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan., Takamura T; Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Ishikawa 920-8640, Japan.
Jazyk:	angličtina
Zdroj:	Endocrinology [Endocrinology] 2023 Apr 17; Vol. 164 (6).
DOI:	10.1210/endocr/bqad065
Abstrakt:	Muscle atrophy is the cause and consequence of obesity. Proteasome dysfunction mediates obesity-induced endoplasmic reticulum (ER) stress and insulin resistance in the liver and adipose tissues. However, obesity-associated regulation of proteasome function and its role in the skeletal muscles remains underinvestigated. Here, we established skeletal muscle-specific 20S proteasome assembly chaperone-1 (PAC1) knockout (mPAC1KO) mice. A high-fat diet (HFD) activated proteasome function by ∼8-fold in the skeletal muscles, which was reduced by 50% in mPAC1KO mice. mPAC1KO induced unfolded protein responses in the skeletal muscles, which were reduced by HFD. Although the skeletal muscle mass and functions were not different between the genotypes, genes involved in the ubiquitin proteasome complex, immune response, endoplasmic stress, and myogenesis were coordinately upregulated in the skeletal muscles of mPAC1KO mice. Therefore, we introduced an immobilization-induced muscle atrophy model in obesity by combining HFD and immobilization. mPAC1KO downregulated atrogin-1 and MuRF1, together with their upstream Foxo1 and Klf15, and protected against disused skeletal muscle mass reduction. In conclusion, obesity elevates proteasome functions in the skeletal muscles. PAC1 deficiency protects mice from immobilization-induced muscle atrophy in obesity. These findings suggest obesity-induced proteasome activation as a possible therapeutic target for immobilization-induced muscle atrophy. (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)
Databáze:	MEDLINE
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