Downregulation of E3 ubiquitin ligases and mitophagy-related genes in skeletal muscle of physically inactive, frail older women: A cross-sectional comparison
Open accessAbstract
BACKGROUND AND OBJECTIVES: Reduced lean mass and physical function is a characteristic of frailty. However, it is currently unknown if proteolysis through the E3 ubiquitin ligases and the autophagic lysosomal pathway is dysregulated in inactive frail older women. The purpose of this study was to determine the expression of key markers of ubiquitin-mediated and autophagic lysosomal proteolysis in inactive (N = 7) compared with active (N = 7) older women. METHODS: Strength, mobility, leg lean mass, and physical activity assessment were used to characterize activity levels and frailty in older women. Vastus lateralis biopsies were collected after an overnight fast and were assessed for gene and protein targets related to E3 ubiquitin ligases and the autophagic lysosomal system. RESULTS: We found that AMP-activated protein kinase alpha (Thr172) was increased (p = .045), and forkhead box O3A (FOXO3A) gene expression (p = .047) was lower in inactive frail older women. Foxo3a (Ser253), Beclin1 (Ser93/96), and class III phosphatidylinositol-3-kinase (VPS34) protein expression were not different between the groups (p > .05). Neural precursor cell-expressed developmentally downregulated protein 4, muscle ring finger 1, muscle atrophy F-box, and the autophagy/mitophagy gene expression markers, Beclin1, autophagy-related-7, BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3), dynamin-related protein 1, and Parkinson protein 2 (PARKIN) were lower in inactive frail older women (p < .05). Autophagy/mitophagy markers were positively correlated with the 6-minute walk and leg lean mass (p < .05). CONCLUSIONS: We conclude that physical inactivity in frail older women is associated with a downregulation of ubiquitin-mediated and autophagic lysosomal skeletal muscle gene expression, perhaps related to low muscle mass and poor physical function.
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A majority of evidence shows that better muscle and mitochondrial health occur concomitantly with elevated markers of mitochondrial fission, mitophagy receptors, and oxidative phosphorylation in human skeletal muscle of older adults who are active or who completed an exercise training program.
“A majority of evidence shows that better muscle and mitochondrial health occur concomitantly with elevated markers of mitochondrial fission, mitophagy receptors, and oxidative phosphorylation in human skeletal muscle of older adults who are active (Balan et al., 2019; Drummond et al., 2014; Tezze et al., 2017) or who completed an exercise training program (Konopka 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 Drummond et al., 2014
Autophagy-related genes are downregulated in inactive older women.
“In addition, it has been reported that autophagy‐related genes, such as BNIP3, BECLIN‐1, ATG7 and PARK2 (the gene coding for Parkin), are downregulated in inactive older women (Drummond et al. 2014).”
From Parkin overexpression protects from ageing‐related loss of muscle mass and strength (2019) · cites this paper as Drummond et al. 2014
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 [150]
Inactive old women have significantly lower expression levels of Bnip3, Beclin 1, Atg7, and Park2 compared to a more active cohort.
“In line with this finding, it has been reported that inactive old women have significantly lower expression levels of Bnip3, Beclin 1, Atg7, and Park2 (the gene coding for Parkin), compared to a more active cohort [150].”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [150]
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“…itantly with elevated markers of mitochondrial fission, mitophagy receptors, and oxidative phosphorylation in human skeletal muscle of older adults who are active (Balan et al., 2019; Drummond et al., 2014 ; Tezze et al., 2017 ) or who completed an exercise training program (Konopka et al., 2014 ).”
Background
- Authors
- Drummond, M. J., Addison, O., Brunker, L., Hopkins, P. N., McClain, D. A., LaStayo, P. C., & Marcus, R. L.
- Affiliations
- University of Utah (US)
- Venue
- The Journals of Gerontology Series A: Biological Sciences and Medical Sciences
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-02-13
- Volume
- 69
- Issue
- 8
- Pages
- 1040-1048
- ISSN
- 1079-5006 (ISSN-L)
- 1758-535X
- PMC
- PMC4111292
- OpenAlex
- W2170660730
- Cited by
- 161
- References
- 39
- Citations by year
- 2026: 10 · 2025: 14 · 2024: 20 · 2023: 13 · 2022: 17 · 2021: 19 · 2020: 12 · 2019: 11 · 2018: 13 · 2017: 13 · 2016: 14 · 2015: 2 · 2014: 2
- FWCI
- 4.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journals of Gerontology Series A (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5ul1tr001067-05)
- U.S. Public Health Service (1ULTR001067)
- National Institute on Aging (K01AG038556)
- National Center for Advancing Translational Sciences (UL1-TR001067)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- frailty, physical inactivity, older women, E3 ubiquitin ligase, mitophagy, autophagy, skeletal muscle, ubiquitin-mediated proteolysis, AMPK, FOXO3, Beclin-1, Vps34, muscle atrophy, leg lean mass, physical function, vastus lateralis
- MeSH terms
- Tripartite Motif Proteins, Beclin-1, Forkhead Box Protein O3, Nedd4 Ubiquitin Protein Ligases, Aged, Aged, 80 and over, Cross-Sectional Studies, Female, Humans, Membrane Proteins, Microtubule-Associated Proteins, Muscle Proteins, Muscular Atrophy, Phosphorylation, Proto-Oncogene Proteins, Down-Regulation, Gene Expression, Genes, Tumor Suppressor, Frail Elderly, Muscle, Skeletal, GTP Phosphohydrolases, Mitochondrial Proteins, Dynamins, Ubiquitin-Protein Ligases, SKP Cullin F-Box Protein Ligases, Apoptosis Regulatory Proteins, Forkhead Transcription Factors, AMP-Activated Protein Kinases, Sarcopenia, Endosomal Sorting Complexes Required for Transport, Proteolysis, Mitophagy
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