Multiple environmental and genetic factors influence skeletal muscle PGC-1α and PGC-1β gene expression in twins

Ling, Charlotte; Poulsen, Pernille; Carlsson, Enar; Ridderstråle, Martin; Almgren, Peter; Wojtaszewski, Jørgen F. P.; Beck‐Nielsen, Henning; Groop, Leif; Vaag, Allan

doi:10.1172/jci200421889

Cited by 154 publications

(136 citation statements)

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“…Additionally, more recent whole genome association studies (WGAS) have not only confirmed the previous associated gene regions, but also identified variants in FTO, CDKN2A/CDKN2B, IGF2BP2, CDKAL1, HHEX, WFS1 and SLC30A8 as being associated with type 2 diabetes [9]. We have previously shown that an agedependent decrease in skeletal muscle PGC-1α and PGC-1β expression is partially heritable and influenced by the PGC-1α Gly482Ser and PGC-1β Ala203Pro polymorphisms [10,11]. In addition, insulin-resistant offspring of patients with type 2 diabetes were suggested to have impaired mitochondrial function in skeletal muscle [12].…”

Section: Introductionmentioning

confidence: 61%

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

et al. 2008

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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 V : O 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. Diabetologia (2008) 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.

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Section: Introductionmentioning

confidence: 61%

“…Selection criteria for the young and elderly twins have been previously described and their clinical characteristics are described in Table 1 [10,17,18].…”

Section: Participantsmentioning

confidence: 99%

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

et al. 2008

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“…Physical activity and, especially, its high-intensity component are known to be lower in the elderly (Meijer et al 2001). Hence, in young adults, the increased risk for developing type 2 diabetes associated with the GA/AA genotypes in rs8192678 may be compensated for by an increased time spent on high-intensity physical activity (Ling et al 2004). …”

Section: Discussionmentioning

confidence: 99%

Heritability and genetic etiology of habitual physical activity: a twin study with objective measures

et al. 2014

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Twin studies with objective measurements suggest habitual physical activity (HPA) are modestly to highly heritable, depending on age. We aimed to confirm or refute this finding and identify relevant genetic variants using a candidate gene approach. HPA was measured for 14 days with a validated triaxial accelerometer (Tracmor) in two populations: (1) 28 monozygotic and 24 dizygotic same-sex twin pairs (aged 22 ± 5 years, BMI 21.8 ± 3.4 kg/m 2 , 21 male, 31 female pairs); (2) 52 and 65 unrelated men and women (aged 21 ± 2 years, BMI 22.0 ± 2.5 kg/m 2 ). Single nucleotide polymorphisms (SNPs) in PPARD, PPARGC1A, NRF1 and MTOR were considered candidates. Association analyses were performed for both groups separately followed by meta-analysis. Structural equation modeling shows significant familiality for HPA, consistent with a role for additive genetic factors (heritability 57 %, 95 % CI 32-74 %, AE model) or common environmental factors (47 %, 95 % CI 23-65 %, CE model). A moderate heritability was observed for the time spent on low-and high-intensity physical activity (P B 0.05), but could not be confirmed for the time spent on moderate-intensity physical activity. For PPARD, each additional effect allele was inversely associated with HPA (P B 0.01; rs2076168 allele C) or tended to be associated with HPA (P B 0.05; rs2267668 allele G). Linkage disequilibrium existed between those two SNPs (alleles A/G and A/C, respectively) and meta-analysis showed that carriers of the AA GC haplotype were less physically active than carriers of the AA AA and AA AC haplotypes combined (P = 0.017). For PPARGC1A, carriers of AA in rs8192678 spent more time on high-intensity physical activity than GG carriers (P = 0.001). No associations were observed with SNPs in NRF1 and MTOR. In conclusion, HPA may be modestly heritable, which is confirmed by an association with variants in PPARD.

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“…In isolated rodent islets and clonal β-cells, overexpression of PGC-1α suppresses insulin secretion (Yoon et al, 2003). We have shown that the PGC-1α Gly482Ser variant influences the expression of this gene in human pancreatic islets and in human skeletal muscle (Ling et al, 2004). We also demonstrated that expression of PGC-1α is reduced in islets from patients with Type 2 Diabetes compared with control subjects and that the expression level correlates with glucose-stimulated insulin secretion.…”

Section: Control Of Mitochondria By Nuclear Encoded Genesmentioning

confidence: 82%

“…Finally, aging is a determining factor in the pathogenesis of Type 2 Diabetes. Also in this process, there is a strong focus on mitochondrial metabolism Ling et al, 2004;Ling et al, 2007;Trifunovic and Larsson, 2008). For all these reasons, mitochondria are a primary concern in the disease processes of Type 2 Diabetes.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial dysfunction in pancreatic β-cells in Type 2 Diabetes

Mulder

Ling

2009

Molecular and Cellular Endocrinology

105

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Mitochondrial metabolism controls insulin secretion from the pancreatic β-cell. Type 2 Diabetes evolves when the β-cells fail to release appropriate amounts of insulin, causing metabolic dysregulation and hyperglycemia. It is attractive to assume that mitochondrial dysfunction plays a decisive role in these processes. Indeed, while being a rare condition, genetically determined dysfunction of mitochondria causes a Type 2 Diabetes-like syndrome.Here, we review what is known about mitochondrial dysfunction in the β-cell in Type 2Diabetes. The focus is on observations in humans but relevant studies in animal models of the disease are discussed. A particular emphasis is placed on changes in metabolic enzymes and function in β-cell mitochondria and how altered structure of the organelle appears to facilitate its function. These molecular processes are subject to tight genetic as well as epigenetic control. Variations and implications of these mechanisms are reviewed. The emerging picture is that alterations in mitochondria may be a culprit in the pathogenetic processes culminating in Type 2 Diabetes. Such processes may prove to be targets for therapeutic interventions in the disease.

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Multiple environmental and genetic factors influence skeletal muscle PGC-1α and PGC-1β gene expression in twins

Cited by 154 publications

References 45 publications

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

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

Heritability and genetic etiology of habitual physical activity: a twin study with objective measures

Mitochondrial dysfunction in pancreatic β-cells in Type 2 Diabetes

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