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01.07.2008 | Article

Age influences DNA methylation and gene expression of COX7A1 in human skeletal muscle

verfasst von: T. Rönn, P. Poulsen, O. Hansson, J. Holmkvist, P. Almgren, P. Nilsson, T. Tuomi, B. Isomaa, L. Groop, A. Vaag, C. Ling

Erschienen in: Diabetologia | Ausgabe 7/2008

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Abstract

Aims/hypothesis

Reduced oxidative capacity of the mitochondria in skeletal muscle has been suggested to contribute to insulin resistance and type 2 diabetes. Moreover, a set of genes influencing oxidative phosphorylation (OXPHOS) is downregulated in diabetic muscle. Here we studied whether genetic, epigenetic and non-genetic factors influence a component of the respiratory chain, COX7A1, previously shown to be downregulated in skeletal muscle from patients with type 2 diabetes. The specific aims were to: (1) evaluate the impact of genetic (single nucleotide polymorphisms [SNPs]), epigenetic (DNA methylation) and non-genetic (age) factors on the expression of COX7A1 in human skeletal muscle; and (2) investigate whether common variants in the COX7A1 gene are associated with increased risk of type 2 diabetes.

Methods

COX7A1 mRNA expression was analysed in muscle biopsies from young (n = 110) and elderly (n = 86) non-diabetic twins and related to measures of in vivo metabolism. Genetic variants (three SNPs) from the COX7A1 locus were genotyped in the twins and in two independent type 2 diabetes case–control cohorts (n = 1466 and 6380, respectively). DNA methylation of the COX7A1 promoter was analysed in a subset of twins (ten young, ten elderly) using bisulphite sequencing.

Results

While DNA methylation of the COX7A1 promoter was increased in muscle from elderly compared with young twins (19.9 ± 8.3% vs 1.8 ± 2.7%; p = 0.035), the opposite was found for COX7A1 mRNA expression (elderly 1.00 ± 0.05 vs young 1.68 ± 0.06; p = 0.0005). The heritability of COX7A1 expression was estimated to be 50% in young and 72% in elderly twins. One of the polymorphisms investigated, rs753420, influenced basal COX7A1 expression in muscle of young (p = 0.0001) but not of elderly twins. The transcript level of COX7A1 was associated with increased in vivo glucose uptake and \(\mathop V\limits^ \cdot {\text{O}}_{{\text{2max}}} \) (p = 0.009 and p = 0.001, respectively). We did not observe any genetic association between COX7A1 polymorphisms and type 2 diabetes after correcting for multiple testing.

Conclusions/interpretation

Our results provide further evidence for age as a factor influencing DNA methylation and expression of OXPHOS genes, and thereby in vivo metabolism.

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Titel: Age influences DNA methylation and gene expression of COX7A1 in human skeletal muscle
verfasst von: T. Rönn
P. Poulsen
O. Hansson
J. Holmkvist
P. Almgren
P. Nilsson
T. Tuomi
B. Isomaa
L. Groop
A. Vaag
C. Ling
Publikationsdatum: 01.07.2008
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 7/2008
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-008-1018-8

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