Genetic variation in ATP5O is associated with skeletal muscle ATP50 mRNA expression and glucose uptake in young twins
Open accessAbstract
BACKGROUND: Impaired oxidative capacity of skeletal muscle mitochondria contribute to insulin resistance and type 2 diabetes (T2D). Furthermore, mRNA expression of genes involved in oxidative phosphorylation, including ATP5O, is reduced in skeletal muscle from T2D patients. Our aims were to investigate mechanisms regulating ATP5O expression in skeletal muscle and association with glucose metabolism, and the relationship between ATP5O single nucleotide polymorphisms (SNPs) and risk of T2D. METHODOLOGY/PRINCIPAL FINDINGS: ATP5O mRNA expression was analyzed in skeletal muscle from young (n = 86) and elderly (n = 68) non-diabetic twins before and after a hyperinsulinemic euglycemic clamp. 11 SNPs from the ATP5O locus were genotyped in the twins and a T2D case-control cohort (n = 1466). DNA methylation of the ATP5O promoter was analyzed in twins (n = 22) using bisulfite sequencing. The mRNA level of ATP5O in skeletal muscle was reduced in elderly compared with young twins, both during basal and insulin-stimulated conditions (p<0.0005). The degree of DNA methylation around the transcription start of ATP5O was <1% in both young and elderly twins and not associated with mRNA expression (p = 0.32). The mRNA level of ATP5O in skeletal muscle was positively related to insulin-stimulated glucose uptake (regression coefficient = 6.6; p = 0.02). Furthermore, two SNPs were associated with both ATP5O mRNA expression (rs12482697: T/T versus T/G; p = 0.02 and rs11088262: A/A versus A/G; p = 0.004) and glucose uptake (rs11088262: A/A versus A/G; p = 0.002 and rs12482697: T/T versus T/G; p = 0.005) in the young twins. However, we could not detect any genetic association with T2D. CONCLUSIONS/SIGNIFICANCE: Genetic variation and age are associated with skeletal muscle ATP5O mRNA expression and glucose disposal rate, suggesting that combinations of genetic and non-genetic factors may cause the reduced expression of ATP5O in T2D muscle. These findings propose a role for ATP5O, in cooperation with other OXPHOS genes, in the regulation of in vivo glucose metabolism.
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Aging is linked to impaired oxidative function in parallel with reductions in OXPHOS gene expression, including COX7A1, NDUFB6, and ATP50.
“Aging is also linked to impaired oxidative function (140) in parallel with reductions in OXPHOS gene expression, including COX7A1, NDUFB6, and ATP50 (136 -138).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [138]
Similar patterns are observed for the complex I gene NDUFB6 and the ATP synthase component ATP5O.
“Similar patterns are observed for the complex I gene NDUFB6 (137) and the ATP synthase component ATP5O (138).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [138]
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- Authors
- Rönn, T., Poulsen, P., Tuomi, T., Isomaa, B., Groop, L., Vaag, A., & Ling, C.
- Affiliations
- Lund University (SE)
- University of Helsinki (FI)
- Corresponding author
- Rönn, Tina
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2009-03-10
- Volume
- 4
- Issue
- 3
- Pages
- e4793
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2651471
- OpenAlex
- W2071893827
- Cited by
- 36
- References
- 34
- Citations by year
- 2026: 2 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 5 · 2020: 4 · 2019: 3 · 2018: 1 · 2016: 2 · 2015: 1 · 2014: 1 · 2013: 2 · 2012: 4
- FWCI
- 1.34
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Työväentutkimus Vuosikirja (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion, other-oa)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Sundhed og Sygdom, Det Frie Forskningsråd
- Lunds Universitet
- Knut och Alice Wallenbergs Stiftelse
- Novo Nordisk
- Vetenskapsrådet
- Diabetesforeningen
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
- Keywords
- skeletal muscle, glucose uptake, type 2 diabetes, single nucleotide polymorphisms, DNA methylation, oxidative phosphorylation, mitochondrial oxidative capacity, insulin resistance, hyperinsulinemic-euglycemic clamp, age-related gene expression, genetic association, twins, mRNA expression
- MeSH terms
- Adult, Age Factors, Diabetes Mellitus, Type 2, Female, Genotype, Glucose, Humans, Male, Middle Aged, Oxidative Phosphorylation, Oxidative Phosphorylation Coupling Factors, Promoter Regions, Genetic, RNA, Messenger, Twins, Genetic Variation, Down-Regulation, Muscle, Skeletal, DNA Methylation, Polymorphism, Single Nucleotide, Mitochondrial Proton-Translocating ATPases
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