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Genetic variation in ATP5O is associated with skeletal muscle ATP50 mRNA expression and glucose uptake in young twins.

Rönn T, Poulsen P, Tuomi T, Isomaa B, Groop L, Vaag A, Ling C - PLoS ONE (2009)

Bottom Line: The mRNA level of ATP5O in skeletal muscle was reduced in elderly compared with young twins, both during basal and insulin-stimulated conditions (p<0.0005).Furthermore, two SNPs were associated with both ATP5O mRNA expression (rs12482697: T/T versus T/G; p = 0.02 and rs11088262: A/A versus A/G; p = 0.004) and glucose uptake (rs11088262: A/A versus A/G; p = 0.002 and rs12482697: T/T versus T/G; p = 0.005) in the young twins.Genetic variation and age are associated with skeletal muscle ATP5O mRNA expression and glucose disposal rate, suggesting that combinations of genetic and non-genetic factors may cause the reduced expression of ATP5O in T2D muscle.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, CRC Malmö University Hospital, Lund University, Malmö, Sweden. tina.ronn@med.lu.se

ABSTRACT

Background: Impaired oxidative capacity of skeletal muscle mitochondria contribute to insulin resistance and type 2 diabetes (T2D). Furthermore, mRNA expression of genes involved in oxidative phosphorylation, including ATP5O, is reduced in skeletal muscle from T2D patients. Our aims were to investigate mechanisms regulating ATP5O expression in skeletal muscle and association with glucose metabolism, and the relationship between ATP5O single nucleotide polymorphisms (SNPs) and risk of T2D.

Methodology/principal findings: ATP5O mRNA expression was analyzed in skeletal muscle from young (n = 86) and elderly (n = 68) non-diabetic twins before and after a hyperinsulinemic euglycemic clamp. 11 SNPs from the ATP5O locus were genotyped in the twins and a T2D case-control cohort (n = 1466). DNA methylation of the ATP5O promoter was analyzed in twins (n = 22) using bisulfite sequencing. The mRNA level of ATP5O in skeletal muscle was reduced in elderly compared with young twins, both during basal and insulin-stimulated conditions (p<0.0005). The degree of DNA methylation around the transcription start of ATP5O was <1% in both young and elderly twins and not associated with mRNA expression (p = 0.32). The mRNA level of ATP5O in skeletal muscle was positively related to insulin-stimulated glucose uptake (regression coefficient = 6.6; p = 0.02). Furthermore, two SNPs were associated with both ATP5O mRNA expression (rs12482697: T/T versus T/G; p = 0.02 and rs11088262: A/A versus A/G; p = 0.004) and glucose uptake (rs11088262: A/A versus A/G; p = 0.002 and rs12482697: T/T versus T/G; p = 0.005) in the young twins. However, we could not detect any genetic association with T2D.

Conclusions/significance: Genetic variation and age are associated with skeletal muscle ATP5O mRNA expression and glucose disposal rate, suggesting that combinations of genetic and non-genetic factors may cause the reduced expression of ATP5O in T2D muscle. These findings propose a role for ATP5O, in cooperation with other OXPHOS genes, in the regulation of in vivo glucose metabolism.

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Chromosomal position of ATP5O and location of analyzed SNPs.
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pone-0004793-g001: Chromosomal position of ATP5O and location of analyzed SNPs.

Mentions: Genomic DNA was extracted from blood using conventional methods. Genotype data covering the ATP5O locus (chr21:34230028–34187627, 20 kb upstream and 10 kb downstream of the ATP5O gene transcript, Fig. 1) was downloaded from the International HapMap project (last accessed March 2008) [16] for the CEPH (Utah residents with ancestry from northern and western Europe) population. 33 SNPs with minor allele frequency >1% were found. Linkage disequilibrium (LD) structure between these SNPs was analyzed using Haploview [17] and 11 tag SNPs [18] were selected such that all alleles are correlated at an r2>0.9 (Fig. 1). These SNPs were genotyped using iPLEX™ assays and matrixassisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry on the MassARRAY® system (Sequenom, San Diego, CA, USA) in the Swegene laboratory in Malmö. 3 SNPs failed this method and were analyzed by allelic discrimination using TaqMan® SNP Genotyping Assays on the ABI7900 (Applied Biosystems). Primer sequences and additional genotyping details are available from the authors.


Genetic variation in ATP5O is associated with skeletal muscle ATP50 mRNA expression and glucose uptake in young twins.

Rönn T, Poulsen P, Tuomi T, Isomaa B, Groop L, Vaag A, Ling C - PLoS ONE (2009)

Chromosomal position of ATP5O and location of analyzed SNPs.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2651471&req=5

pone-0004793-g001: Chromosomal position of ATP5O and location of analyzed SNPs.
Mentions: Genomic DNA was extracted from blood using conventional methods. Genotype data covering the ATP5O locus (chr21:34230028–34187627, 20 kb upstream and 10 kb downstream of the ATP5O gene transcript, Fig. 1) was downloaded from the International HapMap project (last accessed March 2008) [16] for the CEPH (Utah residents with ancestry from northern and western Europe) population. 33 SNPs with minor allele frequency >1% were found. Linkage disequilibrium (LD) structure between these SNPs was analyzed using Haploview [17] and 11 tag SNPs [18] were selected such that all alleles are correlated at an r2>0.9 (Fig. 1). These SNPs were genotyped using iPLEX™ assays and matrixassisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry on the MassARRAY® system (Sequenom, San Diego, CA, USA) in the Swegene laboratory in Malmö. 3 SNPs failed this method and were analyzed by allelic discrimination using TaqMan® SNP Genotyping Assays on the ABI7900 (Applied Biosystems). Primer sequences and additional genotyping details are available from the authors.

Bottom Line: The mRNA level of ATP5O in skeletal muscle was reduced in elderly compared with young twins, both during basal and insulin-stimulated conditions (p<0.0005).Furthermore, two SNPs were associated with both ATP5O mRNA expression (rs12482697: T/T versus T/G; p = 0.02 and rs11088262: A/A versus A/G; p = 0.004) and glucose uptake (rs11088262: A/A versus A/G; p = 0.002 and rs12482697: T/T versus T/G; p = 0.005) in the young twins.Genetic variation and age are associated with skeletal muscle ATP5O mRNA expression and glucose disposal rate, suggesting that combinations of genetic and non-genetic factors may cause the reduced expression of ATP5O in T2D muscle.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, CRC Malmö University Hospital, Lund University, Malmö, Sweden. tina.ronn@med.lu.se

ABSTRACT

Background: Impaired oxidative capacity of skeletal muscle mitochondria contribute to insulin resistance and type 2 diabetes (T2D). Furthermore, mRNA expression of genes involved in oxidative phosphorylation, including ATP5O, is reduced in skeletal muscle from T2D patients. Our aims were to investigate mechanisms regulating ATP5O expression in skeletal muscle and association with glucose metabolism, and the relationship between ATP5O single nucleotide polymorphisms (SNPs) and risk of T2D.

Methodology/principal findings: ATP5O mRNA expression was analyzed in skeletal muscle from young (n = 86) and elderly (n = 68) non-diabetic twins before and after a hyperinsulinemic euglycemic clamp. 11 SNPs from the ATP5O locus were genotyped in the twins and a T2D case-control cohort (n = 1466). DNA methylation of the ATP5O promoter was analyzed in twins (n = 22) using bisulfite sequencing. The mRNA level of ATP5O in skeletal muscle was reduced in elderly compared with young twins, both during basal and insulin-stimulated conditions (p<0.0005). The degree of DNA methylation around the transcription start of ATP5O was <1% in both young and elderly twins and not associated with mRNA expression (p = 0.32). The mRNA level of ATP5O in skeletal muscle was positively related to insulin-stimulated glucose uptake (regression coefficient = 6.6; p = 0.02). Furthermore, two SNPs were associated with both ATP5O mRNA expression (rs12482697: T/T versus T/G; p = 0.02 and rs11088262: A/A versus A/G; p = 0.004) and glucose uptake (rs11088262: A/A versus A/G; p = 0.002 and rs12482697: T/T versus T/G; p = 0.005) in the young twins. However, we could not detect any genetic association with T2D.

Conclusions/significance: Genetic variation and age are associated with skeletal muscle ATP5O mRNA expression and glucose disposal rate, suggesting that combinations of genetic and non-genetic factors may cause the reduced expression of ATP5O in T2D muscle. These findings propose a role for ATP5O, in cooperation with other OXPHOS genes, in the regulation of in vivo glucose metabolism.

Show MeSH
Related in: MedlinePlus