Increased sensitivity to mitochondrial permeability transition and myonuclear translocation of endonuclease G in atrophied muscle of physically active older humans

Gouspillou, Gilles; Sgarioto, Nicolas; Kapchinsky, Sophia; Purves‐Smith, Fennigje; Norris, Brandon; Pion, Charlotte H.; Barbat‐Artigas, Sebastien; Lemieux, Francois; Taivassalo, Tanja; Morais, José A.; Aubertin‐Leheudre, Mylene; Hepple, Russell T.

doi:10.1096/fj.13-242750

Cited by 217Mitochondrial Function and PathologyMuscle Physiology and DisordersAutophagy in Disease and Therapy

Increased sensitivity to mitochondrial permeability transition and myonuclear translocation of endonuclease G in atrophied muscle of physically active older humans

Gouspillou, Gilles, Sgarioto, Nicolas, Kapchinsky, Sophia, Purves‐Smith, Fennigje, Norris, Brandon, Pion, Charlotte H., Barbat‐Artigas, Sebastien, Lemieux, Francois +4 more·2014·The FASEB Journal

DOI 10.1096/fj.13-242750

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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.—Gouspillou, G., Sgarioto, N., Kapchinsky, S., Purves‐Smith, F., Norris, B., Pion, C. H., Barbat‐Artigas, S., Lemieux, R, Taivassalo, T., Morais, J. A., Aubertin‐Leheudre, M., Hepple, R. T. Increased sensitivity to mitochondrial permeability transition and myonuclear translocation of endonuclease G in atrophied muscle of physically active older humans. FASEB J. 28, 28–1621 (1633). www.fasebj.org

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Others have reported an impairment in mitophagy even in muscle from physically active older adults.
“However, others have reported an impairment in mitophagy even in muscle from physically active older adults (Gouspillou et al., 2014).”
From Autophagy gene expression in skeletal muscle of older individuals is associated with physical performance, muscle volume and mitochondrial function in the study of muscle, mobility and aging ( <scp>SOMMA</scp> ) (2024) · cites this paper as Gouspillou et al., 2014
Mitophagy may be impaired with aging.
“suggesting that mitophagy may be impaired with aging.”
From Chronological Age Does not InfluenceEx-vivoMitochondrial Respiration and Quality Control in Skeletal Muscle (2016) · cites this paper as [2]
Recent studies investigating whether mitochondrial quality control is influenced by aging have produced inconclusive results.
“Recent studies have investigated whether mitochondrial quality control is influenced by aging, but the results are not conclusive and remain to be elucidated (1,2,25,35,36).”
From Chronological Age Does not InfluenceEx-vivoMitochondrial Respiration and Quality Control in Skeletal Muscle (2016) · cites this paper as [2]
Gouspillou et al. reported no differences in Parkin expression between young and older muscles, but found that the Parkin-to-VDAC ratio is decreased in the older subjects.
“Additionally, Gouspillou et al. (2) reported no differences in Parkin expression between young and older muscles, but found that the Parkin-to-VDAC ratio is decreased in the older subjects”
From Chronological Age Does not InfluenceEx-vivoMitochondrial Respiration and Quality Control in Skeletal Muscle (2016) · cites this paper as [2]
Several studies found no effect of age on mitochondrial oxidative capacity.
“several studies found no effect of age on mitochondrial oxidative capacity [[345], [346], [347], [348], [349]]”
From Global consensus on optimal exercise recommendations for enhancing healthy longevity in older adults (ICFSR) (2025) · cites this paper as [345]

Aging is associated with a decline in mitochondrial bioenergetics in rodents and humans.
“Indeed, many studies conducted in both rodents and humans have shown that aging is associated with a decline in mitochondrial bioenergetics [9,10,11].”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [9]
The mitochondrial permeability transition pore (mPTP) becomes dysfunctional in old rodents and humans.
“Several studies have also shown that the mitochondrial permeability transition pore (mPTP) becomes dysfunctional in old rodents and humans [9,12,13,14].”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [9]
Mitophagy might be impaired during muscle aging in humans.
“suggesting that mitophagy might be impaired during muscle aging in humans [9]”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [9]
The ratio of Parkin to VDAC is significantly reduced in atrophied muscles of old men compared to muscles of young men.
“In humans, we reported that the ratio of Parkin to VDAC (voltage-dependent anion channel) is significantly reduced in atrophied muscles of old men compared to muscles of young men, suggesting that mitophagy might be impaired during muscle aging in humans [9].”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [9]
Stress-induced damage to mitochondrial membranes contributes to sensitization of the mPTP.
“Stress-induced damage to mitochondrial membranes (40, 108, 144, 147) contributes to sensitization of the mitochondrial permeability transition pore (mPTP) (44).”
From Mitochondria initiate and regulate sarcopenia (2017) · cites this paper as [44]
Apoptosis signaling has been reported in muscle and neuronal cells of aged rodents and humans.
“Apoptosis signaling has been reported in muscle and neuronal cells of aged rodents (4, 7, 26, 34, 47, 77, 88, 130), and humans (44, 145).”
From Mitochondria initiate and regulate sarcopenia (2017) · cites this paper as [44]

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Authors: Gouspillou, G., Sgarioto, N., Kapchinsky, S., Purves‐Smith, F., Norris, B., Pion, C. H., Barbat‐Artigas, S., Lemieux, F., Taivassalo, T., Morais, J. A., Aubertin‐Leheudre, M., & Hepple, R. T.
Affiliations: Université du Québec à Montréal (CA)
McGill University Health Centre (CA)
McGill University (CA)
Department of Kinesiology McGill University Montreal Quebec Canada
Département de Kinanthropologie Université du Québec à Montreal Montreal Quebec Canada
Corresponding author: Hepple, Russell T.
ORCID: Gouspillou, Gilles
Pion, Charlotte H.
Taivassalo, Tanja
Morais, José A.
Hepple, Russell T.
Venue: The FASEB Journal
Publisher: Wiley
Published: 2013-12-26
Volume: 28
Issue: 4
Pages: 1621-1633
ISSN: 0892-6638 (ISSN-L)
1530-6860
DOI: 10.1096/fj.13-242750
OpenAlex: W2066734635
Cited by: 217
References: 68
Citations by year: 2026: 9 · 2025: 13 · 2024: 20 · 2023: 18 · 2022: 14 · 2021: 26 · 2020: 17 · 2019: 18 · 2018: 24 · 2017: 19 · 2016: 21 · 2015: 14 · 2014: 3
FWCI: 5.68
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: The FASEB Journal (publishedVersion)
PubMed (publishedVersion)
Funders: Canadian Institutes of Health Research (MOP125986, MOP119583)
Réseau québécois de recherche sur le vieillissement
McGill University Health Centre
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords: mitochondrial permeability transition, endonuclease G, skeletal muscle aging, mitochondrial dysfunction, mitochondrial apoptosis, mitophagy, Parkin, voltage-dependent anion channel, calcium retention capacity, mitochondrial uncoupling, reactive oxygen species, mitochondrial respiration, muscle atrophy, physically active older adults, vastus lateralis
MeSH terms: Mitochondrial Permeability Transition Pore, Adult, Aged, Aging, Biopsy, Calcium, Cell Nucleus, Endodeoxyribonucleases, Humans, Magnetic Resonance Imaging, Mitochondria, Muscular Atrophy, Permeability, Immunoblotting, Apoptosis, Reactive Oxygen Species, Muscle, Skeletal, Active Transport, Cell Nucleus, Mitochondrial Membrane Transport Proteins, Young Adult

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Increased sensitivity to mitochondrial permeability transition and myonuclear translocation of endonuclease G in atrophied muscle of physically active older humans

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