COX7A1
Cytochrome c oxidase subunit 7A1, mitochondrial precursor (Cytochrome c oxidase subunit VIIa-heart) (Cytochrome c oxidase subunit VIIa-H) (Cytochrome c oxidase subunit VIIa-muscle) (Cytochrome c oxidase subunit VIIa-M) [COX7AH]
PublicationsПравить
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. 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. 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. Our results provide further evidence for age as a factor influencing DNA methylation and expression of OXPHOS genes, and thereby in vivo metabolism.
MeSH Terms
- Adult
- Aged
- Aging
- Biopsy
- DNA Methylation
- Diabetes Mellitus, Type 2
- Electron Transport Complex IV
- Epigenesis, Genetic
- Female
- Gene Expression Regulation
- Genetic Predisposition to Disease
- Humans
- Insulin Resistance
- Male
- Middle Aged
- Muscle, Skeletal
- Oxidative Phosphorylation
- Polymorphism, Single Nucleotide
- Promoter Regions, Genetic
- RNA, Messenger
- Risk Factors