Decline in Skeletal Muscle Mitochondrial Respiratory Chain Function: Possible Factor in Ageing

Trounce, Ian A.; Byrne, Edward; Marzuki, Sangkot

doi:10.1016/s0140-6736(89)92143-0

Cited by 664 publications

(356 citation statements)

References 25 publications

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“…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.…”

supporting

confidence: 93%

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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confidence: 93%

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

et al. 2008

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“…37 Isolated mitochondria from elderly participants showed decreased state 3 (activated) mitochondrial respiration. 38 Taken together, these data indicate that ATP depletion caused by mitochondrial dysfunction might be a cause of sarcopenia. Therefore, ATP depletion in skeletal muscle might be a common feature of muscle atrophy.…”

Section: Discussionmentioning

confidence: 78%

Overexpression of Peroxisome Proliferator-Activated Receptor γ Co-Activator-1α Leads to Muscle Atrophy with Depletion of ATP

Miura¹,

Tomitsuka

Kamei

et al. 2006

The American Journal of Pathology

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Peroxisome proliferator-activated receptor-␥ co-activator-1␣ (PGC-1␣) is a key nuclear receptor co-activator for mitochondrial biogenesis. Here we report that overexpression of PGC-1␣ in skeletal muscles increased mitochondrial number and caused atrophy of skeletal muscle, especially type 2B fiber-rich muscles (gastrocnemius, quadriceps, and plantaris). Muscle atrophy became evident at 25 weeks of age, and a portion of the muscle was replaced by adipocytes. Mice showed increased energy expenditure and reduced body weight; thyroid hormone levels were normal. Mitochondria exhibited normal respiratory chain activity per mitochondrion; however, mitochondrial respiration was not inhibited by an ATP synthase inhibitor, oligomycin, clearly indicating that oxidative phosphorylation was uncoupled. Accordingly, ATP content in gastrocnemius was markedly reduced. A similar phenotype is observed in Luft's disease, a mitochondrial disorder that involves increased uncoupling of respiration and muscle atrophy. Our results indicate that overexpression of PGC-1␣ in skeletal muscle increases not only mitochondrial biogenesis but also uncoupling of respiration, resulting in muscle atrophy.

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“…An age-related reduction in expression of OXPHOS genes is likely to reduce mitochondrial function and insulin action in muscle and eventually increase the risk of developing T2DM. In support of this hypothesis, aging has been associated with decreased OXPHOS expression and mitochondrial oxidative capacity in muscle (2,14). Furthermore, healthy elderly individuals show increased fat accumulation, reduced mitochondrial activity, and reduced insulin-stimulated glucose uptake in skeletal muscle compared with young subjects (15).…”

Section: Discussionmentioning

confidence: 97%

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

Ling¹,

Poulsen²,

Simonsson³

et al. 2007

J. Clin. Invest.

174

156

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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

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Decline in Skeletal Muscle Mitochondrial Respiratory Chain Function: Possible Factor in Ageing

Cited by 664 publications

References 25 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

Overexpression of Peroxisome Proliferator-Activated Receptor γ Co-Activator-1α Leads to Muscle Atrophy with Depletion of ATP

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

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