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

Caterina Tezze, Vanina Romanello, Maria Andrea Desbats, Gian Paolo Fadini, Mattia Albiero, Giulia Favaro, Stefano Ciciliot, Maria Eugenia Soriano, Valeria Morbidoni, Cristina Cerqua, Stefan Loefler, Helmut Kern, Claudio Franceschi, Stefano Salvioli, Maria Conte, Bert Blaauw, Sandra Zampieri, Leonardo Salviati, Luca Scorrano, Marco Sandri

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1374-1389.e6
JournalCell Metabolism
Volume25
Issue number6
DOIs
Publication statusPublished - Jun 6 2017

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Tezze, C., Romanello, V., Desbats, M. A., Fadini, G. P., Albiero, M., Favaro, G., Ciciliot, S., Soriano, M. E., Morbidoni, V., Cerqua, C., Loefler, S., Kern, H., Franceschi, C., Salvioli, S., Conte, M., Blaauw, B., Zampieri, S., Salviati, L., Scorrano, L., & Sandri, M. (2017). Age-Associated Loss of OPA1 in Muscle Impacts Muscle Mass, Metabolic Homeostasis, Systemic Inflammation, and Epithelial Senescence. Cell Metabolism, 25(6), 1374-1389.e6. https://doi.org/10.1016/j.cmet.2017.04.021