title: Age influences DNA methylation and gene expression of COX7A1 in human skeletal muscle.
abstract: OBJECTIVE
  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
  Our results provide further evidence for age as a factor influencing DNA methylation and expression of OXPHOS genes, and thereby in vivo metabolism.
authors.affiliation: Department of Clinical Sciences, CRC Malmö University Hospital, Lund University, 205 02, Malmö, Sweden.
authors.forename: T
authors.initials: T
authors.lastname: Rönn
authors.forename: P
authors.initials: P
authors.lastname: Poulsen
authors.forename: O
authors.initials: O
authors.lastname: Hansson
authors.forename: J
authors.initials: J
authors.lastname: Holmkvist
authors.forename: P
authors.initials: P
authors.lastname: Almgren
authors.forename: P
authors.initials: P
authors.lastname: Nilsson
authors.forename: T
authors.initials: T
authors.lastname: Tuomi
authors.forename: B
authors.initials: B
authors.lastname: Isomaa
authors.forename: L
authors.initials: L
authors.lastname: Groop
authors.forename: A
authors.initials: A
authors.lastname: Vaag
authors.forename: C
authors.initials: C
authors.lastname: Ling
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000235:genetics*; D001706:Biopsy; D019175:DNA Methylation; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology; D010085:Oxidative Phosphorylation; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012307:Risk Factors
chemical_list: D012333:RNA, Messenger; C513901:COX7A1 protein, human; D003576:Electron Transport Complex IV