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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Published in:Cell metabolism Vol. 25; no. 6; p. 1374
Main Authors: 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
Format: Journal Article
Language:English
Published: United States 06.06.2017
Subjects:
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
Online Access:Get more information
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Summary: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.
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ISSN:1932-7420
1932-7420
DOI:10.1016/j.cmet.2017.04.021