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

作者：Ronn T; Poulsen P; Hansson O; Holmkvist J; Almgren P; Nilsson P; Tuomi T; Isomaa B; Groop L; Vaag A; Ling C^*

来源：Diabetologia, 2008, 51(7): 1159-1168.

DOI：10.1007/s00125-008-1018-8

• COX7A1
• DNA methylation
• epigenetic
• gene expression
• genetic
• glucose metabolism
• oxidative phosphorylation
• polymorphism
• skeletal muscle
• type 2 diabetes

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 VO(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.

• 出版日期2008-7