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

Rönn, Tina LU ; Poulsen, P; Hansson, Ola LU ; Holmkvist, Johan LU ; Almgren, Peter LU ; Nilsson, P; Tuomi, Tiinamaija LU ; Isomaa, B; Groop, Leif LU and Vaag, A, et al. (2008) In Diabetologia 51(7). p.1159-1168
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... (More)
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 [Formula: see text] (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. (Less)
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Contribution to journal
publication status
published
subject
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Diabetologia
volume
51
issue
7
pages
1159 - 1168
publisher
Springer Verlag
external identifiers
  • wos:000256428000012
  • pmid:18488190
  • scopus:44749089106
ISSN
1432-0428
DOI
10.1007/s00125-008-1018-8
language
English
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yes
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f9a27a0e-6295-4086-847b-7be5502324c9 (old id 1154006)
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http://www.ncbi.nlm.nih.gov/pubmed/18488190?dopt=Abstract
date added to LUP
2008-06-05 08:59:35
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2017-10-22 04:56:18
@article{f9a27a0e-6295-4086-847b-7be5502324c9,
  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 [Formula: see text] (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.},
  author       = {Rönn, Tina and Poulsen, P and Hansson, Ola and Holmkvist, Johan and Almgren, Peter and Nilsson, P and Tuomi, Tiinamaija and Isomaa, B and Groop, Leif and Vaag, A and Ling, Charlotte},
  issn         = {1432-0428},
  language     = {eng},
  number       = {7},
  pages        = {1159--1168},
  publisher    = {Springer Verlag},
  series       = {Diabetologia},
  title        = {Age influences DNA methylation and gene expression of COX7A1 in human skeletal muscle.},
  url          = {http://dx.doi.org/10.1007/s00125-008-1018-8},
  volume       = {51},
  year         = {2008},
}