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

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          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


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

          • Muscle OPA1 controls general metabolism and epithelial senescence via FGF21

          • Inhibition of muscle OPA1 induces a systemic pro-inflammatory status

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


          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.

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          Most cited references 17

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          Organelle isolation: functional mitochondria from mouse liver, muscle and cultured fibroblasts.

          Mitochondria participate in key metabolic reactions of the cell and regulate crucial signaling pathways including apoptosis. Although several approaches are available to study mitochondrial function in situ are available, investigating functional mitochondria that have been isolated from different tissues and from cultured cells offers still more unmatched advantages. This protocol illustrates a step-by-step procedure to obtain functional mitochondria with high yield from cells grown in culture, liver and muscle. The isolation procedures described here require 1-2 hours, depending on the source of the organelles. The polarographic analysis can be completed in 1 hour.
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            Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration.

            Autophagy is crucial in the turnover of cell components, and clearance of damaged organelles by the autophagic-lysosomal pathway is essential for tissue homeostasis. Defects of this degradative system have a role in various diseases, but little is known about autophagy in muscular dystrophies. We have previously found that muscular dystrophies linked to collagen VI deficiency show dysfunctional mitochondria and spontaneous apoptosis, leading to myofiber degeneration. Here we demonstrate that this persistence of abnormal organelles and apoptosis are caused by defective autophagy. Skeletal muscles of collagen VI-knockout (Col6a1(-/-)) mice had impaired autophagic flux, which matched the lower induction of beclin-1 and BCL-2/adenovirus E1B-interacting protein-3 (Bnip3) and the lack of autophagosomes after starvation. Forced activation of autophagy by genetic, dietary and pharmacological approaches restored myofiber survival and ameliorated the dystrophic phenotype of Col6a1(-/-) mice. Furthermore, muscle biopsies from subjects with Bethlem myopathy or Ullrich congenital muscular dystrophy had reduced protein amounts of beclin-1 and Bnip3. These findings indicate that defective activation of the autophagic machinery is pathogenic in some congenital muscular dystrophies.
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              Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice.

              Mitochondrial morphology is shaped by fusion and division of their membranes. Here, we found that adult myocardial function depends on balanced mitochondrial fusion and fission, maintained by processing of the dynamin-like guanosine triphosphatase OPA1 by the mitochondrial peptidases YME1L and OMA1. Cardiac-specific ablation of Yme1l in mice activated OMA1 and accelerated OPA1 proteolysis, which triggered mitochondrial fragmentation and altered cardiac metabolism. This caused dilated cardiomyopathy and heart failure. Cardiac function and mitochondrial morphology were rescued by Oma1 deletion, which prevented OPA1 cleavage. Feeding mice a high-fat diet or ablating Yme1l in skeletal muscle restored cardiac metabolism and preserved heart function without suppressing mitochondrial fragmentation. Thus, unprocessed OPA1 is sufficient to maintain heart function, OMA1 is a critical regulator of cardiomyocyte survival, and mitochondrial morphology and cardiac metabolism are intimately linked.

                Author and article information

                Cell Metab
                Cell Metab
                Cell Metabolism
                Cell Press
                06 June 2017
                06 June 2017
                : 25
                : 6
                : 1374-1389.e6
                [1 ]Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy
                [2 ]Department of Biomedical Science, University of Padova, via G. Colombo 3, 35100 Padova, Italy
                [3 ]Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Via Giustiniani 3, 35128 Padova, Italy
                [4 ]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 ]Istituto di Ricerca Pediatria, IRP, Città della Speranza, Corso Stati Uniti 4, 35129 Padova, Italy
                [9 ]Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada
                Author notes
                []Corresponding author luca.scorrano@ 123456unipd.it
                [∗∗ ]Corresponding author marco.sandri@ 123456unipd.it

                These authors contributed equally


                Lead Contact

                © 2017 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).


                Cell biology

                opa1, mitochondria, inflammation, foxo, sarcopenia, fgf21, aging, muscle, oxidative stress


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