Intensified mitophagy in skeletal muscle with aging is downregulated by PGC-1alpha overexpression in vivo
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ABSTRACT Mitochondrial dysfunction plays an important role in the etiology of age‐related muscle atrophy known as sarcopenia. PGC‐1&agr; is positioned at the center of crosstalk in regulating mitochondrial quality control, but its role in mitophagy in aged skeletal muscle is currently unclear. The present study investigated the effects of aging and PGC‐1&agr; overexpression via in vivo DNA transfection on key mitophagy protein markers, as well as mitochondrial dynamics related proteins, metabolic function and antioxidant capacity in mouse muscle. C57BL/6J mice at the age of 2 mo (young, Y; N = 14) and 24 mo (old, O; N = 14) were transfected in vivo with either PGC‐1&agr; DNA (OE, N = 7) or GFP (N = 7) into the tibialis anterior (TA) muscle followed by electroporation. PINK1 and Parkin protein contents were 3.6 and 1.4‐fold higher (P < 0.01), whereas mitochondrial ubiquitination (Ub) increased 1.5‐fold (P < 0.05), in O vs. Y mice. PGC‐1 OE suppressed PINK and Parkin protein levels by 50–60% (P < 0.01), and decreased Ub by 20% (P < 0.05) in old mice. Aging significantly increased the protein content of LC3II (30%, P < 0.05), p62 (42%, P < 0.05), RheB (5.5‐fold, P < 0.01), Beclin‐1 (3‐fold, P < 0.01) and Mfn2 (˜4‐fold, P < 0.01) in the TA muscle. However, these age‐related increases in mitophagy markers were attenuated by PGC‐1&agr; OE. Furthermore, aging dramatically increased Fis‐1 protein content by 14‐fold (P < 0.01), along with a severe reduction of citrate synthase activity (64%, P < 0.01) and cytochrome c oxidase subunit IV (COXIV) protein content (85%, P < 0.01). PGC‐1&agr; OE mitigated the age effects on Fis‐1 and Drp‐1 (P < 0.05). Moreover, PGC‐1&agr; OE enhanced mitochondrial oxidative function and antioxidant enzyme activities, and decreased lipid peroxidation and inner membrane damage found in old mice (P < 0.01). In summary, our data demonstrate that mitophagy protein expression in skeletal muscle was enhanced at old age driven possibly by increased mitochondrial dysfunction, damage, and fission. PGC‐1&agr; OE was effective in ameliorating mitochondrial deficits but did not restore muscle fiber atrophy. Graphical abstract Figure. No Caption available. HighlightsAging upregulates mitophagy‐related proteins in mouse skeletal muscle.Overexpression of PGC‐1&agr; ameliorates mitophagic pathway and mitochondrial quality control in aged muscle.Overexpression of PGC‐1&agr; did not protect against age‐related loss of muscle mass and fiber size.
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Overexpression of PGC-1α increases mitochondrial protein content and antioxidant enzyme activity, modifies gene expression, attenuating the impact of aging on muscle tissue.
“Overexpression of PGC-1α increases mitochondrial protein content and antioxidant enzyme activity, in addition to modifying gene expression, thereby attenuating the impact of aging on muscle tissue [50,51].”
From Exerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis (2025) · cites this paper as [51]
Overexpression of PGC-1α can mitigate the effects of aging on muscle by increasing mitochondrial protein content and antioxidant enzyme activity and altering gene expression to resemble a youthful transcriptome profile.
“In contrast, overexpression of PGC-1α can mitigate the effects of aging on muscle by increasing mitochondrial protein content and antioxidant enzyme activity and altering gene expression to resemble a youthful transcriptome profile (79, 80).”
From From mitochondria to sarcopenia: role of 17β-estradiol and testosterone (2023) · cites this paper as [80]
Mfn2 content in aged rodent skeletal muscle is reported as decreased, unchanged, or increased.
“Mfn2 content has been reported as decreased [34,49,55], unchanged [52], or even increased in aged rodent skeletal muscles [47,50,54].”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [54]
Studies in rodents have reported increased or unchanged Drp1 content in aged skeletal muscles.
“Indeed, studies in rodents have reported increased [49,50,51] or unchanged [34,47,52,54] Drp1 content in aged skeletal muscles.”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [54]
Several studies did not detect any impact of aging on Opa1 content in skeletal muscle of aged mice, rats, and humans.
“However, several studies did not detect any impact of aging on Opa1 content in the skeletal muscle of aged mice [52,54], rats [50], and humans [57,58].”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [54]
Mitophagy-related proteins are decreased in the skeletal muscle of old rodents, although conflicting data exist.
“Although conflicting data exist [54,145,146,147], several studies reported that mitophagy-related proteins are decreased in the skeletal muscle of old rodents [46,120,148,149,150,151,152].”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [54]
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Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging
Leduc-Gaudet, J.-P., Hussain, S. N. A., Barreiro, E., & Gouspillou, G. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22158179 · Cited by 268 · see citing works
“However, several studies did not detect any impact of aging on Opa1 content in the skeletal muscle of aged mice [52,54], rats [50], and humans [57,58].”
BackgroundInfluentialWang, D., Yang, Y., Zou, X., Zhang, J., Zheng, Z., & Wang, Z. (2020) · The Journals of Gerontology Series A · doi:10.1093/gerona/glaa214 · Cited by 87 · see citing works
From mitochondria to sarcopenia: role of 17β-estradiol and testosterone
Tian, X., Lou, S., & Shi, R. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1156583 · Cited by 54 · see citing works
“In contrast, overexpression of PGC-1a can mitigate the effects of aging on muscle by increasing mitochondrial protein content and antioxidant enzyme activity and altering gene expression to resemble a youthful transcriptome profile (79, 80).”
BackgroundExerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis
Wang, J., Jia, D., Zhang, Z., & Wang, D. (2025) · Metabolites · doi:10.3390/metabo15010059 · Cited by 23 · see citing works
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- Authors
- Yeo, D., Kang, C., Gomez-Cabrera, M. C., Vina, J., & Ji, L. L.
- Affiliations
- University of Minnesota (US)
- Inha University (KR)
- Corresponding author
- Ji, Li Li
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2019-01
- Volume
- 130
- Pages
- 361-368
- ISSN
- 0891-5849 (ISSN-L)
- OpenAlex
- W2898849960
- Semantic Scholar
- 7e8e19cbf8cf8d6b17b1030be5f01ef7069ef901
- Cited by
- 137
- References
- 47
- Citations by year
- 2026: 10 · 2025: 29 · 2024: 19 · 2023: 20 · 2022: 14 · 2021: 15 · 2020: 23 · 2019: 6 · 2018: 1
- FWCI
- 8.82
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- Repository of Digital Objects for Teaching Research and Culture (University of Valencia) (submittedVersion, cc-by-nc)
- Funders
- University of Minnesota (146825)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- mitophagy, skeletal muscle aging, sarcopenia, mitochondrial quality control, PINK1, Parkin, mitochondrial ubiquitination, mitochondrial dynamics, Drp1, mitofusin 2, Beclin-1, LC3-II, p62, mitochondrial dysfunction, citrate synthase, cytochrome c oxidase
- MeSH terms
- Beclin-1, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, PTEN-Induced Putative Kinase, Aging, Animals, Gene Expression Regulation, Mitochondria, Protein Kinases, Oxidative Stress, Muscle, Skeletal, GTP Phosphohydrolases, Ubiquitin-Protein Ligases, Mice, Mitochondrial Dynamics, Mitophagy
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