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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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Two ATP5O SNPs are associated with both mRNA expression during clamp and insulin stimulated glucose uptake in young twins.Effects of rs12482697 respective rs11088262 on the ATP50 mRNA levels (a) and glucose uptake (mg·kg LBM−1·min−1, b). Data are expressed as mean±SEM. *p<0.05.
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pone-0004793-g003: Two ATP5O SNPs are associated with both mRNA expression during clamp and insulin stimulated glucose uptake in young twins.Effects of rs12482697 respective rs11088262 on the ATP50 mRNA levels (a) and glucose uptake (mg·kg LBM−1·min−1, b). Data are expressed as mean±SEM. *p<0.05.

Mentions: In order to evaluate the genetic factors influencing ATP5O expression in muscle of the young twins, 11 tag SNPs (Fig. 1) were genotyped and related to gene expression. Two polymorphisms, rs12482697 and rs11088262, influenced the expression of ATP5O in muscle of the young twins (rs12482697: T/T [n = 65] 0.30±0.010 versus T/G [n = 16] 0.25±0.012; p = 0.02 and rs11088262: A/A [n = 70] 0.31±0.012 versus A/G [n = 16] 0.25±0.011; p = 0.004) during the clamp (Fig. 3A). These two polymorphisms are likely to represent the same association, as they show strong LD (r2 = 0.96). rs12482697 is located 5 kb upstream from transcription start whereas rs11088262 is a missense polymorphism in exon 4. However, none of the other SNPs were associated with ATP5O expression in skeletal muscle (data not shown).


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)

Two ATP5O SNPs are associated with both mRNA expression during clamp and insulin stimulated glucose uptake in young twins.Effects of rs12482697 respective rs11088262 on the ATP50 mRNA levels (a) and glucose uptake (mg·kg LBM−1·min−1, b). Data are expressed as mean±SEM. *p<0.05.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0004793-g003: Two ATP5O SNPs are associated with both mRNA expression during clamp and insulin stimulated glucose uptake in young twins.Effects of rs12482697 respective rs11088262 on the ATP50 mRNA levels (a) and glucose uptake (mg·kg LBM−1·min−1, b). Data are expressed as mean±SEM. *p<0.05.
Mentions: In order to evaluate the genetic factors influencing ATP5O expression in muscle of the young twins, 11 tag SNPs (Fig. 1) were genotyped and related to gene expression. Two polymorphisms, rs12482697 and rs11088262, influenced the expression of ATP5O in muscle of the young twins (rs12482697: T/T [n = 65] 0.30±0.010 versus T/G [n = 16] 0.25±0.012; p = 0.02 and rs11088262: A/A [n = 70] 0.31±0.012 versus A/G [n = 16] 0.25±0.011; p = 0.004) during the clamp (Fig. 3A). These two polymorphisms are likely to represent the same association, as they show strong LD (r2 = 0.96). rs12482697 is located 5 kb upstream from transcription start whereas rs11088262 is a missense polymorphism in exon 4. However, none of the other SNPs were associated with ATP5O expression in skeletal muscle (data not shown).

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