Regulation of apoptosis and autophagy in mouse and human skeletal muscle with aging and lifelong exercise training
Abstract
Exercise training has been reported to prevent the age-induced decline in muscle mass and fragmentation of mitochondria, as well as to affect autophagy and mitophagy. The interaction between these pathways during aging as well as the similarity between such changes in human and mouse skeletal muscle is however not fully understood. Therefore the aim of the present study was to test the hypothesis that cellular degradation pathways, including apoptosis, autophagy and mitophagy are coordinately regulated in mouse and human skeletal muscle during aging and lifelong exercise training through a PGC-1α-p53 axis. Muscle samples were obtained from young untrained, aged untrained and aged lifelong exercise trained men, and from whole-body PGC-1α knockout mice and their littermate controls that were either lifelong exercise trained or sedentary young and aged. Lifelong exercise training prevented the aging-induced reduction in PGC-1α, p53 and p21 mRNA as well as the increase in LC3II and BNIP3 protein in mouse skeletal muscle, while aging decreased the BAX/Bcl-2 ratio, LC3I and BAX protein in mouse skeletal muscle without effects of lifelong exercise training. In humans, aging was associated with reduced PGC-1α mRNA as well as decreased p62 and p21 protein in skeletal muscle, while lifelong exercise training increased BNIP3 protein and decreased p53 mRNA. In conclusion, there was a divergent regulation of autophagy and apoptosis in mouse muscle with aging and lifelong exercise training, whereas healthy aged human skeletal muscle seemed rather robust to changes in apoptosis, autophagy and mitophagy markers compared with mouse muscle at the investigated age.
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Systematic physical exercise has been confirmed to slow down progression of aging-related myopathies based on regulation of autophagy.
“Although systematic physical exercise has been confirmed to slow down the progression of aging-related myopathies based on the regulation of autophagy [16], the underlying molecular mechanisms remain controversial.”
From Lifelong Aerobic Exercise Alleviates Sarcopenia by Activating Autophagy and Inhibiting Protein Degradation via the AMPK/PGC-1α Signaling Pathway (2021) · cites this paper as [16]
BNIP3 encodes BCL2 interacting protein 3, which is increased in hypoxic-ischemic-encephalopathy and physiological ageing, and increases in association with cellular senescence especially in cells over-expressing p21 and p16.
“BNIP3 (FC = 1.17, p = 0.04) encodes BCL2 interacting protein 3, which is increased in hypoxic-ischemic-encephalopathy [18] and physiological ageing [31], and has been shown to increase in association with cellular senescence especially in cells over-expressing p21 and p16 [16].”
From Early onset senescence and cognitive impairment in a murine model of repeated mTBI (2021) · cites this paper as [31]
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- Authors
- Dethlefsen, M. M., Halling, J. F., Møller, H. D., Plomgaard, P., Regenberg, B., Ringholm, S., & Pilegaard, H.
- Affiliations
- University of Copenhagen (DK)
- Corresponding author
- Pilegaard, Henriette
- ORCID
- Venue
- Experimental Gerontology
- Publisher
- Elsevier BV
- Published
- 2018-10
- Volume
- 111
- Pages
- 141-153
- ISSN
- 0531-5565 (ISSN-L)
- OpenAlex
- W2884054234
- Cited by
- 54
- References
- 77
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 4 · 2023: 4 · 2022: 9 · 2021: 7 · 2020: 6 · 2019: 11 · 2018: 2
- FWCI
- 2.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Experimental Gerontology (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Danish Medical Research Council (4181-00078)
- Novo Nordisk Foundation (1015389)
- Danish Ministry of Culture Committee on Sports Research (TAKT2013-029)
- Villum Foundation (VKR023513)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- skeletal muscle aging, apoptosis, autophagy, mitophagy, PGC-1α, p53, p21, Bax/Bcl-2 ratio, BNIP3, LC3, p62, muscle mass loss, mitochondrial fragmentation, human-mouse comparison
- MeSH terms
- Autophagy-Related Proteins, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Adult, Aging, Animals, Autophagy, Female, Humans, Male, Mice, Inbred C57BL, Middle Aged, Mitochondria, Physical Conditioning, Animal, RNA, Messenger, Transcription Factors, Exercise, Apoptosis, Mice, Knockout, Muscle, Skeletal, Mice, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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