TY - JOUR
T1 - OPA1 deficiency promotes secretion of FGF21 from muscle that prevents obesity and insulin resistance
AU - Pereira, Renata Oliveira
AU - Tadinada, Satya M.
AU - Zasadny, Frederick M.
AU - Oliveira, Karen Jesus
AU - Pires, Karla Maria Pereira
AU - Olvera, Angela
AU - Jeffers, Jennifer
AU - Souvenir, Rhonda
AU - McGlauflin, Rose
AU - Seei, Alec
AU - Funari, Trevor
AU - Sesaki, Hiromi
AU - Potthoff, Matthew J.
AU - Adams, Christopher M.
AU - Anderson, Ethan J.
AU - Abel, E. Dale
N1 - Funding Information:
This work was supported by NIH grants R01 R01HL108379 and R01DK092065 to E.D.A., who is an established investigator of the American Heart Association (AHA), and AHA Scientist Development Grant 15SDG25710438 (to R.O.P.). We thank Andrew Gulden and Conor Bryant for their technical support. Metabolic phenotyping was performed in the Metabolic Phenotyping Core at the Fraternal Order of Eagles Diabetes Research Center.
Publisher Copyright:
© 2017 The Authors.
PY - 2017/7
Y1 - 2017/7
N2 - 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.
AB - 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.
KW - ER stress
KW - FGF21
KW - Mitochondrial dysfunction
KW - OPA1
KW - Skeletal muscle
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U2 - 10.15252/embj.201696179
DO - 10.15252/embj.201696179
M3 - Article
C2 - 28607005
AN - SCOPUS:85020434687
SN - 0261-4189
VL - 36
SP - 2126
EP - 2145
JO - EMBO Journal
JF - EMBO Journal
IS - 14
ER -