Respiration and phosphorylation of mitochondria isolated from the skeletal muscle of diabetic and normal subjects

Björntorp, Per; Scherstén, T; Fagerberg, Sven‐Erik

doi:10.1007/bf00429867

Cited by 22 publications

(20 citation statements)

References 25 publications

(17 reference statements)

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“…The evidence suggests that reduced expression and activity of enzymes involved in mitochondrial processes, including oxidative phosphorylation, the tricarboxylic acid cycle and betaoxidation of fatty acids, are characteristic of insulin-resistant skeletal muscle [3][4][5][6][7][8][9]. These studies support findings that overall reductions in oxidative and phosphorylation capacity of mitochondria occur in insulin resistance and as part of the ageing process [10][11][12][13][14][15]. Indeed, there is a large body of evidence showing that mitochondrial functional capacity is a key component of the process of ageing, and of the development of a range of diseases.…”

Section: Introductionmentioning

confidence: 54%

“…Numerous studies have demonstrated defects in oxidative pathways in skeletal muscle of subjects with obesity and/or type 2 diabetes [3,4,7,10,11,13], and it has been proposed that impaired bioenergetic capacity of skeletal muscle mitochondria is a key factor in the development of these diseases [7]. Furthermore, reduced mitochondrial function is a hallmark of the ageing process [14,15], and could be a determining factor in the development of insulin resistance and other disorders related with ageing, e.g.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, there is a large body of evidence showing that mitochondrial functional capacity is a key component of the process of ageing, and of the development of a range of diseases. In insulin-resistant skeletal muscle, several studies have demonstrated reductions in the size and number of mitochondria, suggesting that defective mitochondrial biogenesis may be an important factor in the development of obesity and type 2 diabetes [7,10,12,14,16]. Interestingly, several studies have shown evidence of mitochondrial impairment in individuals with increased susceptibility (family history) to type 2 diabetes before the onset of symptoms [8,9], suggesting that mitochondrial dysfunction may contribute to the development of type 2 diabetes.…”

Section: Introductionmentioning

confidence: 99%

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The mitochondrial rhomboid protease PSARL is a new candidate gene for type 2 diabetes

et al. 2005

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Aims/hypothesis: This study aimed to identify genes that are expressed in skeletal muscle, encode proteins with functional significance in mitochondria, and are associated with type 2 diabetes. Methods: We screened for differentially expressed genes in skeletal muscle of Psammomys obesus (Israeli sand rats), and prioritised these on the basis of genomic localisation and bioinformatics analysis for proteins with likely mitochondrial functions. Results: We identified a mitochondrial intramembrane protease, known as presenilins-associated rhomboid-like protein (PSARL) that is associated with insulin resistance and type 2 diabetes. Expression of PSARL was reduced in skeletal muscle of diabetic Psammomys obesus, and restored after exercise training to successfully treat the diabetes. PSARL gene expression in human skeletal muscle was correlated with insulin sensitivity as assessed by glucose disposal during a hyperinsulinaemic-euglycaemic clamp. In 1,031 human subjects, an amino acid substitution (Leu262Val) in PSARL was associated with increased plasma insulin concentration, a key risk factor for diabetes. Furthermore, this variant interacted strongly with age to affect insulin levels, acounting for 5% of the variation in plasma insulin in elderly subjects. Conclusions/interpretation: Variation in PSARL sequence and/or expression may be an important new risk factor for type 2 diabetes and other components of the metabolic syndrome.

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Section: Introductionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The mitochondrial rhomboid protease PSARL is a new candidate gene for type 2 diabetes

et al. 2005

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“…Mitochondrial dysfunction and, in particular, decreases in oxidative capacity have been linked to insulin resistance and type 2 diabetes (42,43). Recent studies also suggest that decreases in the levels of PGC-1␣ and the related coactivator PGC-1␤ contribute to the reduced oxidative capacity in diabetic subjects (23,44).…”

Section: Err␣ Binds To Regulatory Sites In the Promoters Of Atpsyn␤ Andmentioning

confidence: 99%

The estrogen-related receptor α (ERRα) functions in PPARγ coactivator 1α (PGC-1α)-induced mitochondrial biogenesis

Schreiber

Emter

Hock

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

582

500

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Estrogen-related receptor ␣ (ERR␣) is one of the first orphan nuclear receptors to be identified, yet its physiological functions are still unclear. We show here that ERR␣ is an effector of the transcriptional coactivator PGC-1␣ [peroxisome proliferator-activated receptor ␥ (PPAR␥) coactivator 1␣], and that it regulates the expression of genes involved in oxidative phosphorylation and mitochondrial biogenesis. Inhibition of ERR␣ compromises the ability of PGC-1␣ to induce the expression of genes encoding mitochondrial proteins and to increase mitochondrial DNA content. A constitutively active form of ERR␣ is sufficient to elicit both responses. ERR␣ binding sites are present in the transcriptional control regions of ERR␣͞PGC-1␣-induced genes and contribute to the transcriptional response to PGC-1␣. The ERR␣-regulated genes described here have been reported to be expressed at reduced levels in humans that are insulin-resistant. Thus, changes in ERR␣ activity could be linked to pathological changes in metabolic disease, such as diabetes. E strogen-related receptor ␣ (ERR␣, NR3B1) was identified on the basis of its sequence similarity to classical, hormoneregulated steroid receptors (1). Based on its ability to recognize similar DNA sequences as the estrogen receptors, ERR␣ has been proposed to modulate estrogen signaling (2-5). ERR␣ may also regulate bone formation, given that it is highly expressed at ossification sites, promotes osteoblast differentiation in vitro, and activates the promoter of the bone matrix protein osteopontin (6, 7). Finally, ERR␣ may regulate fatty acid oxidation. Consistent with this function, ERR␣ is prominently expressed in tissues with high capacity for ␤-oxidation of fatty acids, such as brown fat, heart, muscle, and kidney, and induces the expression of the medium-chain acyl-CoA dehydrogenase gene (8,9).A better understanding of the transcriptional programs and cellular pathways that depend on ERR␣ has been hampered by the lack of tools to regulate the activity of this receptor. Despite the high similarity between ERR␣ and other ligand-dependent nuclear receptors, it is not clear whether ERR␣ activity is regulated by small lipophilic ligands. Compounds that inhibit ERR␣-dependent transcription, such as toxaphene, chlordane, and diethylstilbestrol, have been described (10, 11). However, these compounds are not specific enough for ERR␣ to facilitate studies of its cellular function. Recently, we demonstrated that the transcriptional coactivator peroxisome proliferator-activated receptor ␥ (PPAR␥) coactivator 1␣ (PGC-1␣) regulates ERR␣ function (12). PGC-1␣ induces the expression of ERR␣ and interacts physically with ERR␣, enabling it to activate transcription (12, 13). These findings suggest that PGC-1␣ can be used as a protein ''ligand'' to regulate ERR␣-dependent transcription and study ERR␣ function.PGC-1␣ has been identified as a tissue-specific coactivator of nuclear receptors (14-16). The expression of PGC-1␣ is most prominent in tissues with high energy demands, similar to the ex...

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“…19 Several investigations have indicated that the mitochondrial respiratory chain may have a direct role in metabolic disorders such as insulin resistance and type 2 diabetes. 20,21 The biogenesis of the respiratory chain is uniquely dependent on the coordinated expression of both nuclear-and mitochondrial-encoded subunits. However, only a minority of the respiratory chain subunits (13 of about 100) are encoded by mitochondrial DNA, but these subunits are nevertheless essentialFas disruption of mitochondrial DNA expression leads to severely impaired respiratory chain function that is in turn linked to metabolic disorders.…”

Section: Genes and Signaling Pathways In Batmentioning

confidence: 99%

Brown adipose tissue in humans

Enerbäck

2010

Int J Obes

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Obesity is endemic in many regions of the world and a forerunner of several serious and sometimes fatal diseases such as ischemic heart disease, stroke, kidney failure and neoplasia. Although we know its originFit results when energy intake exceeds energy expenditureFat present, the only proven therapy is bariatric surgery. This is a major abdominal procedure that, for reasons that are largely unknown (it cannot be explained solely by a reduction in ventricular volume), significantly reduces energy intake, but because of cost and limited availability, it will most likely be reserved for only a small fraction of those who stand to gain from effective antiobesity treatment. Clearly, alternative ways to treat obesity are needed. Another way to combat excessive accumulation of white adipose tissue would be to increase energy expenditure. Rodents, hibernators and human infants all have a specialized tissueFbrown adipose tissue (BAT)Fwith the unique capacity to regulate energy expenditure by a process called adaptive thermogenesis. This process depends on the expression of uncoupling protein-1 (UCP1), which is a unique marker for BAT. UCP1 is an inner mitochondrial membrane protein that short circuits the mitochondrial proton gradient, so that oxygen consumption is no longer coupled to adenosine triphosphate synthesis. As a consequence, heat is generated. Mice lacking ucp-1 are severely compromised in their ability to maintain normal body temperature when acutely exposed to cold and they are also prone to become obese. We have shown that, in mice, BAT protects against diet-induced obesity, insulin resistance and type 2 diabetes. This is based on prevention of excessive accumulation of triglyceride in non-adipose tissues such as muscle and liver. Ectopic triglyceride storage at these locations is associated with initiation of insulin resistance and, ultimately, development of type 2 diabetes.

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Respiration and phosphorylation of mitochondria isolated from the skeletal muscle of diabetic and normal subjects

Cited by 22 publications

References 25 publications

The mitochondrial rhomboid protease PSARL is a new candidate gene for type 2 diabetes

The mitochondrial rhomboid protease PSARL is a new candidate gene for type 2 diabetes

The estrogen-related receptor α (ERRα) functions in PPARγ coactivator 1α (PGC-1α)-induced mitochondrial biogenesis

Brown adipose tissue in humans

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