title: Increased sensitivity to mitochondrial permeability transition and myonuclear translocation of endonuclease G in atrophied muscle of physically active older humans.
abstract: Mitochondrial dysfunction is implicated in skeletal muscle atrophy and dysfunction with aging, with strong support for an increased mitochondrial-mediated apoptosis in sedentary rodent models. Whether this applies to aged human muscle is unknown, nor is it clear whether these changes are caused by sedentary behavior. Thus, we examined mitochondrial function [respiration, reactive oxygen species (ROS) emission, and calcium retention capacity (CRC)] in permeabilized myofibers obtained from vastus lateralis muscle biopsies of healthy physically active young (23.7±2.7 yr; mean±SD) and older (71.2±4.9 yr) men. Although mitochondrial ROS and maximal respiratory capacity were unaffected, the acceptor control ratio was reduced by 18% with aging, suggesting mild uncoupling of oxidative phosphorylation. CRC was reduced by 50% with aging, indicating sensitization of the mitochondrial permeability transition pore (mPTP) to apoptosis. Consistent with the mPTP sensitization, older muscles showed a 3-fold greater fraction of endonuclease G (a mitochondrial proapoptotic factor)-positive myonuclei. Aged muscles also had lower mitophagic potential, based on a 43% reduction in Parkin to the voltage-dependent anion channel (VDAC) protein ratio. Collectively, these results show that mitochondrial-mediated apoptotic signaling is increased in older human muscle and suggest that accumulation of dysfunctional mitochondria with exaggerated apoptotic sensitivity is due to impaired mitophagy.
authors.affiliation: 1Department of Critical Care Medicine, Royal Victoria Hospital, 687 Pine Ave. W., Montreal, QC, Canada H3A 1A. russell.hepple@mcgill.ca.
authors.forename: Gilles
authors.initials: G
authors.lastname: Gouspillou
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sgarioto
authors.forename: Sophia
authors.initials: S
authors.lastname: Kapchinsky
authors.forename: Fennigje
authors.initials: F
authors.lastname: Purves-Smith
authors.forename: Brandon
authors.initials: B
authors.lastname: Norris
authors.forename: Charlotte H
authors.initials: CH
authors.lastname: Pion
authors.forename: Sébastien
authors.initials: S
authors.lastname: Barbat-Artigas
authors.forename: Francois
authors.initials: F
authors.lastname: Lemieux
authors.forename: Tanja
authors.initials: T
authors.lastname: Taivassalo
authors.forename: José A
authors.initials: JA
authors.lastname: Morais
authors.forename: Mylène
authors.initials: M
authors.lastname: Aubertin-Leheudre
authors.forename: Russell T
authors.initials: RT
authors.lastname: Hepple
mesh_terms: D021581:Active Transport, Cell Nucleus; D000328:Adult; D000368:Aged; D000375:Aging / Q000378:metabolism; D017209:Apoptosis; D001706:Biopsy; D002118:Calcium / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D004706:Endodeoxyribonucleases / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008279:Magnetic Resonance Imaging; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009133:Muscular Atrophy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010539:Permeability; D017382:Reactive Oxygen Species / Q000378:metabolism; D055815:Young Adult
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D004706:Endodeoxyribonucleases; C052391:endonuclease G; D002118:Calcium
keywords: aging; mitophagy; reactive oxygen species; sarcopenia