UCP3 protein expression is lower in type I, IIa and IIx muscle fiber types of endurance-trained compared to untrained subjects

Russell, Aaron P.; Wadley, Glenn D.; Hesselink, Matthijs K. C.; Schaart, Gert; Lo, Sing Kai; Léger, Bertrand; Garnham, Andrew; Kornips, Esther; Cameron‐Smith, David; Giacobino, Jean‐Paul; Muzzin, Patrick; Snow, Rod J.; Schrauwen, Patrick

doi:10.1007/s00424-002-0943-5

Cited by 61 publications

(83 citation statements)

References 44 publications

(54 reference statements)

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“…Recent studies indicate that mitochondria from different fiber types may have different metabolic characteristics. This includes a higher UCP3 content in type 2X fibers in human skeletal muscle (46) and a lower lipid oxidative capacity per mitochondria and higher hydrogen peroxide production in type 2 fibers from rodent muscle (27,47). Correspondingly, we observed a positive association between the proportion of type 1 fibers and mitochondrial respiration with palmitoyl-L-carnitine plus malate and a correlation between type 2X fibers and noncoupled (state 4) respiration.…”

Section: Discussionsupporting

confidence: 56%

Mitochondrial Respiration Is Decreased in Skeletal Muscle of Patients With Type 2 Diabetes

et al. 2007

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We tested the hypothesis of a lower respiratory capacity per mitochondrion in skeletal muscle of type 2 diabetic patients compared with obese subjects. Muscle biopsies obtained from 10 obese type 2 diabetic and 8 obese nondiabetic male subjects were used for assessment of 3-hydroxy-Acyl-CoA-dehydrogenase (HAD) and citrate synthase activity, uncoupling protein (UCP)3 content, oxidative stress measured as 4-hydroxy-2-nonenal (HNE), fiber type distribution, and respiration in isolated mitochondria. Respiration was normalized to citrate synthase activity (mitochondrial content) in isolated mitochondria. Maximal ADPstimulated respiration (state 3) with pyruvate plus malate and respiration through the electron transport chain (ETC) were reduced in type 2 diabetic patients, and the proportion of type 2X fibers were higher in type 2 diabetic patients compared with obese subjects (all P < 0.05). There were no differences in respiration with palmitoyl-Lcarnitine plus malate, citrate synthase activity, HAD activity, UCP3 content, or oxidative stress measured as HNE between the groups. In the whole group, state 3 respiration with pyruvate plus malate and respiration through ETC were negatively associated with A1C, and the proportion of type 2X fibers correlated with markers of insulin resistance (P < 0.05). In conclusion, we provide evidence for a functional impairment in mitochondrial respiration and increased amount of type 2X fibers in muscle of type 2 diabetic patients. These alterations may contribute to the development of type 2 diabetes in humans with obesity. Diabetes 56:1592-1599, 2007 T ype 2 diabetes is characterized by insulin resistance in major metabolic tissues such as skeletal muscle, liver, and adipose tissue, as well as failure of the pancreatic ␤-cells to compensate for this abnormality (1). Skeletal muscle is the major site of glucose disposal in response to insulin and, correspondingly, the major site of insulin resistance in type 2 diabetes (1,2). Despite extensive research, the mechanisms underlying insulin resistance are not fully understood. Indeed, several abnormalities have been identified in insulinresistant muscle including impaired insulin activation of glycogen synthase (1,3), impairment of the proximal components of the insulin signaling cascade (2), and increased intramuscular triglyceride content (4,5). Another important component of insulin resistance appears to be a decreased ability of insulin to regulate fuel utilization (6 -8). In insulin-resistant subjects, this impaired ability to switch from lipid to carbohydrate oxidation in response to insulin has been described as "metabolic inflexibility" of skeletal muscle (8).Being the site of fuel oxidation, the mitochondrion has gained increasing interest in type 2 diabetes research during the last decade. Several studies have indicated a role for mitochondrial dysfunction in the pathogenesis of insulin resistance and type 2 diabetes. This includes reports of a decreased leg lipid oxidation in type 2 diabetes and obesity (9) and a strong neg...

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Section: Discussionsupporting

confidence: 56%

Mitochondrial Respiration Is Decreased in Skeletal Muscle of Patients With Type 2 Diabetes

et al. 2007

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“…Immunofluorescence. Immunfluorescence experiments were performed as reported previously (25). The PGC-1 (sc-5816; Santa Cruz Biotechnologies, San Diego, CA) and PPAR-␣ (Dr. David Bell, The University of Nottingham, U.K.) antibodies, respectively, were diluted 1:200 and 1:500 in PBS containing 0.5% BSA and 0.1% NaN 3 and were visualized separately, using a donkey sense CAT GTG GCA GAA GCA CTA TGT GT 80 60 anti GCC ACC CAC TCT TTG TCA AAG ␤-Actin sense ACT GAC TAC CTC ATG AAG AT 535 56 anti CGT CAT ACT CCT GCT TGC TGA T anti-goat (IgG) and a goat anti-mouse (IgG) antibody, both conjugated with Alexa Fluor 594 (Molecular Probes Europe, Leiden, the Netherlands) at a concentration of 1:500, for 60 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

Endurance Training in Humans Leads to Fiber Type-Specific Increases in Levels of Peroxisome Proliferator-Activated Receptor-γ Coactivator-1 and Peroxisome Proliferator-Activated Receptor-α in Skeletal Muscle

et al. 2003

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The peroxisome proliferator-activated receptor (PPAR)-␥ coactivator-1 (PGC-1) can induce mitochondria biogenesis and has been implicated in the development of oxidative type I muscle fibers. The PPAR isoforms ␣, ␤/␦, and ␥ control the transcription of genes involved in fatty acid and glucose metabolism. As endurance training increases skeletal muscle mitochondria and type I fiber content and fatty acid oxidative capacity, our aim was to determine whether these increases could be mediated by possible effects on PGC-1 or PPAR-␣, -␤/␦, and -␥. Seven healthy men performed 6 weeks of endurance training and the expression levels of PGC-1 and PPAR-␣, -␤/␦, and -␥ mRNA as well as the fiber type distribution of the PGC-1 and PPAR-␣ proteins were measured in biopsies from their vastus lateralis muscle. PGC-1 and PPAR-␣ mRNA expression increased by 2.7-and 2.2-fold (P < 0.01), respectively, after endurance training. PGC-1 expression was 2.2-and 6-fold greater in the type IIa than in the type I and IIx fibers, respectively. It increased by 2.8-fold in the type IIa fibers and by 1.5-fold in both the type I and IIx fibers after endurance training (P < 0.015). PPAR-␣ was 1.9-fold greater in type I than in the II fibers and increased by 3.0-fold and 1.5-fold in these respective fibers after endurance training (P < 0.001). The increases in PGC-1 and PPAR-␣ levels reported in this study may play an important role in the changes in muscle mitochondria content, oxidative phenotype, and sensitivity to insulin known to be induced by endurance training. Diabetes 52:2874 -2881, 2003

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“…Thus, UCP3 is upregulated under conditions of an abundance of fatty acid supply to the mitochondria, such as during fasting (37), high FFA levels (38), acute exercise (39), and high-fat feeding (36,38). On the other hand, downregulation of UCP3 occurs when fatty acid oxidation is increased or plasma FFA levels are lowered, such as with endurance training (40,41) and weight reduction (42). In addition, we recently reported that UCP3 protein content is inversely related to fat oxidative capacity of muscle, indicating an increased need for UCP3 in those muscles with a low-fat oxidative capacity (43).…”

Section: Mitochondrial Damage: a Role For Lipid Peroxides?mentioning

confidence: 99%

“…Thus, the normal physiological response to physical inactivity and/or a low oxidative capacity is an upregulation, not a downregulation, of UCP3. Endurancetrained athletes with a high oxidative capacity are characterized by very low levels of UCP3 when compared with untrained subjects (41). In addition, UCP3 protein levels are highest in muscles with a low oxidative capacity (43).…”

Section: Mitochondrial Damage: a Role For Lipid Peroxides?mentioning

confidence: 99%

Oxidative Capacity, Lipotoxicity, and Mitochondrial Damage in Type 2 Diabetes

2004

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Recent evidence points toward decreased oxidative capacity and mitochondrial aberrations as a major contributor to the development of insulin resistance and type 2 diabetes. In this article we will provide an integrative view on the interrelation between decreased oxidative capacity, lipotoxicity, and mitochondrial aberrations in type 2 diabetes. Type 2 diabetes is characterized by disturbances in fatty acid metabolism and is accompanied by accumulation of fatty acids in nonadipose tissues. In metabolically active tissues, such as skeletal muscle, fatty acids are prone to so-called oxidative damage. In addition to producing energy, mitochondria are also a major source of reactive oxygen species, which can lead to lipid peroxidation. In particular, the mitochondrial matrix, which contains DNA, RNA, and numerous enzymes necessary for substrate oxidation, is sensitive to peroxide-induced oxidative damage and needs to be protected against the formation and accumulation of lipids and lipid peroxides. Recent evidence reports that mitochondrial uncoupling is involved in the protection of the mitochondrial matrix against lipid-induced mitochondrial damage. Disturbances in this protection mechanism can contribute to the development of type 2 diabetes.

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UCP3 protein expression is lower in type I, IIa and IIx muscle fiber types of endurance-trained compared to untrained subjects

Cited by 61 publications

References 44 publications

Mitochondrial Respiration Is Decreased in Skeletal Muscle of Patients With Type 2 Diabetes

Mitochondrial Respiration Is Decreased in Skeletal Muscle of Patients With Type 2 Diabetes

Endurance Training in Humans Leads to Fiber Type-Specific Increases in Levels of Peroxisome Proliferator-Activated Receptor-γ Coactivator-1 and Peroxisome Proliferator-Activated Receptor-α in Skeletal Muscle

Oxidative Capacity, Lipotoxicity, and Mitochondrial Damage in Type 2 Diabetes

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