Age-Associated Loss of OPA1 in Muscle Impacts Muscle Mass, Metabolic Homeostasis, Systemic Inflammation, and Epithelial Senescence

Mitochondrial dysfunction occurs during aging, but its impact on tissue senescence is unknown. Here, we find that sedentary but not active humans display an age-related decline in the mitochondrial protein, optic atrophy 1 (OPA1), that is associated with muscle loss. In adult mice, acute, muscle-spe...

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Vydáno v:	Cell metabolism Ročník 25; číslo 6; s. 1374
Hlavní autoři:	Tezze, Caterina, Romanello, Vanina, Desbats, Maria Andrea, Fadini, Gian Paolo, Albiero, Mattia, Favaro, Giulia, Ciciliot, Stefano, Soriano, Maria Eugenia, Morbidoni, Valeria, Cerqua, Cristina, Loefler, Stefan, Kern, Helmut, Franceschi, Claudio, Salvioli, Stefano, Conte, Maria, Blaauw, Bert, Zampieri, Sandra, Salviati, Leonardo, Scorrano, Luca, Sandri, Marco
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 06.06.2017
Témata:	Aging - genetics Aging - metabolism Aging - pathology Animals Cellular Senescence - genetics Endoplasmic Reticulum Stress - genetics Fibroblast Growth Factors - genetics Fibroblast Growth Factors - metabolism GTP Phosphohydrolases - genetics GTP Phosphohydrolases - metabolism Inflammation - enzymology Inflammation - genetics Inflammation - pathology Mice Muscle, Skeletal - enzymology Muscle, Skeletal - pathology Muscular Atrophy - enzymology Muscular Atrophy - genetics Muscular Atrophy - pathology Organ Size Unfolded Protein Response - genetics FoxO Opa1 inflammation mitochondria muscle aging oxidative stress FGF21 sarcopenia
ISSN:	1932-7420, 1932-7420
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Shrnutí:	Mitochondrial dysfunction occurs during aging, but its impact on tissue senescence is unknown. Here, we find that sedentary but not active humans display an age-related decline in the mitochondrial protein, optic atrophy 1 (OPA1), that is associated with muscle loss. In adult mice, acute, muscle-specific deletion of Opa1 induces a precocious senescence phenotype and premature death. Conditional and inducible Opa1 deletion alters mitochondrial morphology and function but not DNA content. Mechanistically, the ablation of Opa1 leads to ER stress, which signals via the unfolded protein response (UPR) and FoxOs, inducing a catabolic program of muscle loss and systemic aging. Pharmacological inhibition of ER stress or muscle-specific deletion of FGF21 compensates for the loss of Opa1, restoring a normal metabolic state and preventing muscle atrophy and premature death. Thus, mitochondrial dysfunction in the muscle can trigger a cascade of signaling initiated at the ER that systemically affects general metabolism and aging.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1932-7420 1932-7420
DOI:	10.1016/j.cmet.2017.04.021