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EMBO J. 2017 Jul 14;36(14):2126-2145. doi: 10.15252/embj.201696179. Epub 2017 Jun 12.

OPA1 deficiency promotes secretion of FGF21 from muscle that prevents obesity and insulin resistance.

Author information

1
Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, IA, USA.
2
Division of Endocrinology, Metabolism and Diabetes, and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
3
Department of Cell Biology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
4
Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, IA, USA.
5
College of Pharmacy, University of Iowa, Iowa City, IA, USA.
6
Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, IA, USA drcadmin@uiowa.edu.

Abstract

Mitochondrial dynamics is a conserved process by which mitochondria undergo repeated cycles of fusion and fission, leading to exchange of mitochondrial genetic content, ions, metabolites, and proteins. Here, we examine the role of the mitochondrial fusion protein optic atrophy 1 (OPA1) in differentiated skeletal muscle by reducing OPA1 gene expression in an inducible manner. OPA1 deficiency in young mice results in non-lethal progressive mitochondrial dysfunction and loss of muscle mass. Mutant mice are resistant to age- and diet-induced weight gain and insulin resistance, by mechanisms that involve activation of ER stress and secretion of fibroblast growth factor 21 (FGF21) from skeletal muscle, resulting in increased metabolic rates and improved whole-body insulin sensitivity. OPA1-elicited mitochondrial dysfunction activates an integrated stress response that locally induces muscle atrophy, but via secretion of FGF21 acts distally to modulate whole-body metabolism.

KEYWORDS:

ER stress; FGF21; OPA1; mitochondrial dysfunction; skeletal muscle

PMID:
28607005
PMCID:
PMC5510002
DOI:
10.15252/embj.201696179
[Indexed for MEDLINE]
Free PMC Article

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