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

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.

Graphical Abstract

Highlights

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  OPA1 is a physical activity sensor that is downregulated during aging sarcopenia

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  Muscle OPA1 controls general metabolism and epithelial senescence via FGF21

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  Inhibition of muscle OPA1 induces a systemic pro-inflammatory status

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  OPA1 controls protein breakdown/synthesis, muscle stem cells and fiber innervation

Abstract

Aging has been reported to be accompanied by changes in mitochondrial dynamics, but the impact on tissue senescence is unknown. Tezze et al. show that deletion of Opa1 impacts muscle mass, metabolic homeostasis, systemic inflammation, and epithelial senescence and identify FGF21 as the culprit of precocious aging and premature death.