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
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Abstract	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.
AbstractList	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. 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.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.
Author	Morbidoni, Valeria Franceschi, Claudio Tezze, Caterina Desbats, Maria Andrea Albiero, Mattia Cerqua, Cristina Conte, Maria Soriano, Maria Eugenia Salviati, Leonardo Ciciliot, Stefano Salvioli, Stefano Blaauw, Bert Zampieri, Sandra Sandri, Marco Scorrano, Luca Kern, Helmut Fadini, Gian Paolo Loefler, Stefan Romanello, Vanina Favaro, Giulia
Author_xml	– sequence: 1 givenname: Caterina surname: Tezze fullname: Tezze, Caterina organization: Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy; Department of Biomedical Science, University of Padova, via G. Colombo 3, 35100 Padova, Italy – sequence: 2 givenname: Vanina surname: Romanello fullname: Romanello, Vanina organization: Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy; Department of Biomedical Science, University of Padova, via G. Colombo 3, 35100 Padova, Italy – sequence: 3 givenname: Maria Andrea surname: Desbats fullname: Desbats, Maria Andrea organization: Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Via Giustiniani 3, 35128 Padova, Italy – sequence: 4 givenname: Gian Paolo surname: Fadini fullname: Fadini, Gian Paolo organization: Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy – sequence: 5 givenname: Mattia surname: Albiero fullname: Albiero, Mattia organization: Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy – sequence: 6 givenname: Giulia surname: Favaro fullname: Favaro, Giulia organization: Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy; Department of Biomedical Science, University of Padova, via G. Colombo 3, 35100 Padova, Italy – sequence: 7 givenname: Stefano surname: Ciciliot fullname: Ciciliot, Stefano organization: Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy – sequence: 8 givenname: Maria Eugenia surname: Soriano fullname: Soriano, Maria Eugenia organization: Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy; Department of Biology, University of Padova, Via U. Bassi 58B, 35121 Padova, Italy – sequence: 9 givenname: Valeria surname: Morbidoni fullname: Morbidoni, Valeria organization: Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Via Giustiniani 3, 35128 Padova, Italy – sequence: 10 givenname: Cristina surname: Cerqua fullname: Cerqua, Cristina organization: Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Via Giustiniani 3, 35128 Padova, Italy – sequence: 11 givenname: Stefan surname: Loefler fullname: Loefler, Stefan organization: Ludwig Boltzmann Institute of Electrical Stimulation and Physical Rehabilitation, Wilhelminenspital, Montleartstrasse 37, A-1171 Wien, Austria – sequence: 12 givenname: Helmut surname: Kern fullname: Kern, Helmut organization: Ludwig Boltzmann Institute of Electrical Stimulation and Physical Rehabilitation, Wilhelminenspital, Montleartstrasse 37, A-1171 Wien, Austria – sequence: 13 givenname: Claudio surname: Franceschi fullname: Franceschi, Claudio organization: IRCCS, Institute of Neurological Sciences of Bologna, 40139 Bologna, Italy – sequence: 14 givenname: Stefano surname: Salvioli fullname: Salvioli, Stefano organization: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy – sequence: 15 givenname: Maria surname: Conte fullname: Conte, Maria organization: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy – sequence: 16 givenname: Bert surname: Blaauw fullname: Blaauw, Bert organization: Department of Biomedical Science, University of Padova, via G. Colombo 3, 35100 Padova, Italy – sequence: 17 givenname: Sandra surname: Zampieri fullname: Zampieri, Sandra organization: Department of Biomedical Science, University of Padova, via G. Colombo 3, 35100 Padova, Italy – sequence: 18 givenname: Leonardo surname: Salviati fullname: Salviati, Leonardo organization: Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Via Giustiniani 3, 35128 Padova, Italy; Istituto di Ricerca Pediatria, IRP, Città della Speranza, Corso Stati Uniti 4, 35129 Padova, Italy – sequence: 19 givenname: Luca surname: Scorrano fullname: Scorrano, Luca email: luca.scorrano@unipd.it organization: Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy; Department of Biology, University of Padova, Via U. Bassi 58B, 35121 Padova, Italy. Electronic address: luca.scorrano@unipd.it – sequence: 20 givenname: Marco surname: Sandri fullname: Sandri, Marco email: marco.sandri@unipd.it organization: Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy; Department of Biomedical Science, University of Padova, via G. Colombo 3, 35100 Padova, Italy; Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada. Electronic address: marco.sandri@unipd.it
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Keywords	FoxO Opa1 inflammation mitochondria muscle aging oxidative stress FGF21 sarcopenia
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Snippet	Mitochondrial dysfunction occurs during aging, but its impact on tissue senescence is unknown. Here, we find that sedentary but not active humans display an...
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SubjectTerms	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
Title	Age-Associated Loss of OPA1 in Muscle Impacts Muscle Mass, Metabolic Homeostasis, Systemic Inflammation, and Epithelial Senescence
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