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Cell Metab. 2017 Jun 6;25(6):1374-1389.e6. doi: 10.1016/j.cmet.2017.04.021. Epub 2017 May 25.

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

Author information

1
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.
2
Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Via Giustiniani 3, 35128 Padova, Italy.
3
Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy.
4
Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy; Department of Biology, University of Padova, Via U. Bassi 58B, 35121 Padova, Italy.
5
Ludwig Boltzmann Institute of Electrical Stimulation and Physical Rehabilitation, Wilhelminenspital, Montleartstrasse 37, A-1171 Wien, Austria.
6
IRCCS, Institute of Neurological Sciences of Bologna, 40139 Bologna, Italy.
7
Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy.
8
Department of Biomedical Science, University of Padova, via G. Colombo 3, 35100 Padova, Italy.
9
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.
10
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.
11
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.

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.

KEYWORDS:

FGF21; FoxO; Opa1; aging; inflammation; mitochondria; muscle; oxidative stress; sarcopenia

PMID:
28552492
PMCID:
PMC5462533
DOI:
10.1016/j.cmet.2017.04.021
[Indexed for MEDLINE]
Free PMC Article

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