Genetic and epigenetic factors are associated with expression of respiratory chain component NDUFB6 in human skeletal muscle

Abstract

Insulin resistance and type 2 diabetes are associated with decreased expression of genes that regulate oxidative phosphorylation in skeletal muscle. To determine whether this defect might be inherited or acquired, we investigated the association of genetic, epigenetic, and nongenetic factors with expression of NDUFB6, a component of the respiratory chain that is decreased in muscle from diabetic patients. Expression of NDUFB6 was influenced by age, with lower gene expression in muscle of elderly subjects. Heritability of NDUFB6 expression in muscle was estimated to be approximately 60% in twins. A polymorphism in the NDUFB6 promoter region that creates a possible DNA methylation site (rs629566, A/G) was associated with a decline in muscle NDUFB6 expression with age. Although young subjects with the rs629566 G/G genotype exhibited higher muscle NDUFB6 expression, this genotype was associated with reduced expression in elderly subjects. This was subsequently explained by the finding of increased DNA methylation in the promoter of elderly, but not young, subjects carrying the rs629566 G/G genotype. Furthermore, the degree of DNA methylation correlated negatively with muscle NDUFB6 expression, which in turn was associated with insulin sensitivity. Our results demonstrate that genetic, epigenetic, and nongenetic factors associate with NDUFB6 expression in human muscle and suggest that genetic and epigenetic factors may interact to increase age-dependent susceptibility to insulin resistance. IntroductionAlthough reduced physical activity, obesity, and aging increase susceptibility to type 2 diabetes mellitus (T2DM), not all individuals exposed to these risk factors develop the disease. A likely reason is that genetic variation modifies susceptibility to T2DM. Furthermore, the interaction between genetic and nongenetic factors may be even more complex and involve epigenetic factors such as DNA methylation. Insulin-resistant offspring of patients with T2DM and elderly subjects are characterized by impaired mitochondrial function in skeletal muscle (1, 2). Furthermore, nuclear-encoded genes regulating oxidative phosphorylation (OXPHOS), and their transcriptional regulators, PPARγ coactivator 1α (PGC-1α) and PGC-1β, show reduced expression in skeletal muscle of patients with T2DM (3, 4). Nevertheless, it remains unknown whether this is an inherited or acquired defect. We previously showed that an age-dependent decrease in muscle PGC-1α and PGC-1β expression is partially under genetic control and is influenced by the PGC-1α Gly482Ser polymorphism (5). This common variant in the PGC-1α gene has also been associated with increased risk of T2DM (6-8). We hypothesized that the effect of age on mitochondrial function can be determined by both genetic and epigenetic factors. To address this we selected the NDUFB6 gene from the first respiratory complex for further studies, because NDUFB6 is among the set of OXPHOS genes showing significant reduction in muscle from patients with T2DM compared with healthy control subjects and

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

“…Unlike in our previous study [13], we did not observe a significant correlation (r=−0.33) between the level of DNA methylation and gene expression of COX7A1. This could be due to low power or the large variation in DNA methylation observed in the elderly, suggesting that non-genetic factors also might influence the age-related decline in COX7A1 expression.…”

“…A decline in COX7A1 with age may contribute to increased insulin resistance, since elderly twins were more insulinresistant than younger twins and COX7A1 expression in muscle was associated with insulin-stimulated glucose uptake. Our results are thus in line with other reports demonstrating a decrease in mitochondrial OXPHOS activity [39] or expression of OXPHOS genes and insulin-stimulated glucose uptake in muscle of elderly individuals [13,40,41]. Collectively these studies demonstrate that age has a strong influence on expression of OXPHOS genes in human skeletal muscle.…”

“…They are mainly unmethylated, although a subset can show tissue-specific methylation during development [45]. We recently showed increased DNA methylation in another OXPHOS gene, NDUFB6, in muscle of elderly compared with that of young twins; this increase in DNA methylation was associated with an age-related decrease in gene expression [13]. We therefore investigated whether this was also true for the COX7A1 gene region.…”

“…Cytosine residues occurring in CG dinucleotides are targets for DNA methylation in vertebrates and gene expression is often reduced when DNA is methylated in the promoter region. We recently showed that such mechanisms can dramatically change expression of another OXPHOS gene, NDUFB6, during a person's life-time [13].…”

Mitochondrial dysfunction in pancreatic β-cells in Type 2 Diabetes

“…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.…”