Deficiency of electron transport chain in human skeletal muscle mitochondria in type 2 diabetes mellitus and obesity

Ritov, Vladimir B.; Menshikova, Elizabeth V.; Azuma, Koichiro; Wood, Richard J.; Toledo, Frederico G.S.; Goodpaster, Bret H.; Ruderman, Neil B.; Kelley, David E.

doi:10.1152/ajpendo.00317.2009

Cited by 253 publications

(221 citation statements)

References 67 publications

(94 reference statements)

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“…Moreover, significant positive correlations were also observed for summative spot volumes (sum of volumes of all spots with the same identified protein) relating to cytoplasmic malate dehydrogenase (MDH1), an enzyme controlling TCA cycle pool size and providing contractile function [27], and the mitochondrial enzymes ACO2, ATP5A1, ATP5B and GBAS. These results, suggesting reduced TCA cycle and mitochondrial protein content in insulin resistance, are consistent with previous findings of reduced enzyme activities [10,28,29], protein expression [16,17,30], altered phosphorylation [16,31,32], altered transcript levels [10,33,34] or altered flux through mitochondrial ATP synthase [8].…”

Section: Discussionsupporting

confidence: 92%

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The proteomic signature of insulin-resistant human skeletal muscle reveals increased glycolytic and decreased mitochondrial enzymes

et al. 2012

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Aims/hypothesis The molecular mechanisms underlying insulin resistance in skeletal muscle are incompletely understood. Here, we aimed to obtain a global picture of changes in protein abundance in skeletal muscle in obesity and type 2 diabetes, and those associated with whole-body measures of insulin action. Methods Skeletal muscle biopsies were obtained from ten healthy lean (LE), 11 obese non-diabetic (OB), and ten obese type 2 diabetic participants before and after hyperinsulinaemic-euglycaemic clamps. Quantitative proteome analysis was performed by two-dimensional differential-gel electrophoresis and tandem-mass-spectrometry-based protein identification.Results Forty-four protein spots displayed significant (p< 0.05) changes in abundance by at least a factor of 1.5 between groups. Several proteins were identified in multiple spots, suggesting post-translational modifications. Multiple spots containing glycolytic and fast-muscle proteins showed increased abundance, whereas spots with mitochondrial and slow-muscle proteins were downregulated in the OB and obese type 2 diabetic groups compared with the LE group. No differences in basal levels of myosin heavy chains were observed. The abundance of multiple spots representing glycolytic and fast-muscle proteins correlated negatively with insulin action on glucose disposal, glucose oxidation and lipid oxidation, while several spots with proteins J. Giebelstein, G. Poschmann and K. Højlund contributed equally to this work. involved in oxidative metabolism and mitochondrial function correlated positively with these whole-body measures of insulin action. Conclusions/interpretation Our data suggest that increased glycolytic and decreased mitochondrial protein abundance together with a shift in muscle properties towards a fasttwitch pattern in the absence of marked changes in fibretype distribution contribute to insulin resistance in obesity with and without type 2 diabetes. The roles of several differentially expressed or post-translationally modified proteins remain to be elucidated.

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Section: Discussionsupporting

confidence: 92%

“…Inflammation and cytokine signalling appear to be important, and recent studies have linked insulin resistance with mitochondrial dysfunction. This includes reduced mitochondrial content and in some [2][3][4][5], but not all, studies, reduced mitochondrial functional capacity [2,4,[6][7][8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

The proteomic signature of insulin-resistant human skeletal muscle reveals increased glycolytic and decreased mitochondrial enzymes

et al. 2012

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“…Elevated NADH levels indicate that the catabolism in muscle has been enhanced and can facilitate the ETC process, which can further cause oxidative stress (Kussmaul and Hirst, 2006). A high ratio of NADH/NAD is desirable in an anaerobic tissue, which is usually caused by the production of reactive oxygen species in an aerobic tissue that inhibits the tricarboxylic acid cycle and fatty acid oxidation (Ritov et al, 2010;James et al, 2012). The present results showed that LPS treatment caused an increased tendency in the ratio of NADH/NAD.…”

Section: Discussionmentioning

confidence: 55%

Lipopolysaccharide markedly changes glucose metabolism and mitochondrial function in the longissimus muscle of pigs

Sun

Huang

Yin

et al. 2016

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Most previous studies on the effects of lipopolysaccharide (LPS) in pigs focused on the body's immune response, and few reports paid attention to body metabolism changes. To better understand the glucose metabolism changes in skeletal muscle following LPS challenge and to clarify the possible mechanism, 12 growing pigs were employed. Animals were treated with either 2 ml of saline or 15 µg/kg BW LPS, and samples were collected 6 h later. The glycolysis status and mitochondrial function in the longissimus dorsi (LD) muscle of pigs were analyzed. The results showed that serum lactate content and NADH content in LD muscle significantly increased compared with the control group. Most glycolysis-related genes expression, as well as hexokinase, pyruvate kinase and lactic dehydrogenase activity, in LD muscle was significantly higher compared with the control group. Mitochondrial complexes I and IV significantly increased, while mitochondrial ATP concentration markedly decreased. Significantly increased calcium content in the mitochondria was observed, and endoplasm reticulum (ER) stress has been demonstrated in the present study. The results showed that LPS treatment markedly changes glucose metabolism and mitochondrial function in the LD muscle of pigs, and increased calcium content induced by ER stress was possibly involved. The results provide new clues for clarifying metabolic diseases in muscle induced by LPS.Keywords: lipopolysaccharide, mitochondria, glycolysis, pig, inflammation ImplicationsSkeletal muscle is the primary tissue responsible for wholebody energy metabolism. In the current study, we designed the experiment to investigate the effect of lipopolysaccharide (LPS) treatment on muscle energy metabolism in pigs. The results indicated that LPS treatment significantly changed glycolysis level and mitochondrial function in the longissimus dorsi (LD) muscle of pigs, and increased calcium content induced by endoplasm reticulum stress was possibly involved. Understanding these underlying mechanisms may provide new therapeutic strategies for treating metabolic diseases induced by LPS in muscle.

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“…1 -3 Changes in mitochondrial sequence may influence obesity by tightly coupling mitochondrial electron transport, or by interfering with mitochondrial function with subsequent diversion of dietary energy sources towards fat synthesis. 4 Studies of mitochondrial haplogroups, clusters of haplotypes emerging along ancient patterns of human migration, have also suggested a role for sequence variation in environmental adaptations. 5 Conversely, obesity has been widely demonstrated to interfere with mitochondrial function.…”

Section: Introductionmentioning

confidence: 99%

Lack of relationship between mitochondrial heteroplasmy or variation and childhood obesity

et al. 2011

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Mitochondrial electron transport has a central role in regulating energy supply within a cell. We hypothesized that mitochondrial variants or increased levels of mitochondrial heteroplasmy could be associated with common childhood obesity through their effects on mitochondrial function. To investigate this question, we queried two genome-wide genotyped childhood obesity datasets, consisting of 1080 European-American (EA) obese children (defined as BMIX95th percentile) together with 2500 EA lean controls (defined as BMIo50th percentile) and 1479 African-American (AA) obese children and 1575 AA lean controls. Association was not observed between childhood obesity and any of the assayed mitochondrial polymorphisms in either ethnicity. We also found no observable differences in heteroplasmy between each obese and non-obese group. Finally, we analyzed the quantitative mitochondrial genotype cells generated, whether they exceeded the heteroplasmy threshold or not. With this more lenient test, we found six positions with a significant difference between EA cases and controls (Po1 Â 10 À4 ). However, when evaluating the AA data set, no differences were noted at these sites, suggesting that our initial observations were because of chance rather than a meaningful relationship to childhood obesity. As such, it is unlikely that common mitochondrial polymorphisms or heteroplasmy have a role in childhood obesity.

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Deficiency of electron transport chain in human skeletal muscle mitochondria in type 2 diabetes mellitus and obesity

Cited by 253 publications

References 67 publications

The proteomic signature of insulin-resistant human skeletal muscle reveals increased glycolytic and decreased mitochondrial enzymes

The proteomic signature of insulin-resistant human skeletal muscle reveals increased glycolytic and decreased mitochondrial enzymes

Lipopolysaccharide markedly changes glucose metabolism and mitochondrial function in the longissimus muscle of pigs

Lack of relationship between mitochondrial heteroplasmy or variation and childhood obesity

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