Downregulation of uncoupling protein-3 in vivo is linked to changes in muscle mitochondrial energy metabolism as a result of capsiate administration

2007 ◽  
Vol 292 (5) ◽  
pp. E1474-E1482 ◽  
Author(s):  
B. Faraut ◽  
B. Giannesini ◽  
V. Matarazzo ◽  
T. Marqueste ◽  
C. Dalmasso ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Mechanical Performance ◽  
Uncoupling Protein ◽  
Control Group ◽  
Muscle Stimulation ◽  
Mitochondrial Uncoupling ◽  
Mitochondrial Energy Metabolism ◽  
Atp Production ◽  
Uncoupling Protein 3

Although it has been suggested that the skeletal muscle mitochondrial uncoupling protein-3 (UCP3) is involved in regulating energy expenditure, its role is still poorly understood. In the present study, we aimed at investigating noninvasively, using magnetic resonance techniques, metabolic changes occurring in exercising muscle as a result of capsiate treatment, which has been previously linked to UCP3 upregulation. We showed that capsiate ingestion strongly reduced UCP3 gene expression in rat gastrocnemius muscle. This large underexpression was accompanied by a significant increase in the rate of mitochondrial ATP production and phosphocreatine level both at rest and during muscle stimulation. Similarly, the stimulation-induced ATP fall and ADP accumulation were significantly less after capsiate administration than in untreated rats. The larger oxidative ATP production rate could not be explained by a proportional decrease in the anaerobic component, i.e., glycolysis and phosphocreatine breakdown. In addition, the mechanical performance was not affected by capsiate administration. Finally, the plasma free fatty acid (FFA) level increased in capsiate-treated rats, whereas no significant change was observed after muscle stimulation in the control group. Considering the corresponding enhanced UCP3 mRNA expression occurring in the control group after muscle stimulation, one can suggest that changes in FFA level and UCP3 mRNA expression are not mechanistically correlated. Overall, we have shown that capsiate administration induced a UCP3 downregulation coupled with an increased mitochondrial ATP synthesis, whereas the muscle force-generating capacity was unchanged. This suggests that a decrease in muscle efficiency and/or additional noncontractile ATP-consuming mechanisms result from UCP3 downregulation.

Abstract 16: Progressive Alterations Of Mitochondrial Bioenergetics In The Kidney During The Development Of Salt-induced Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Namrata Tomar ◽  
Sunil M Kandel ◽  
Xiao Zhang ◽  
Nadezhda Zheleznova ◽  
Allen W Cowley ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Complex Disease ◽  
Atp Synthesis ◽  
Control Group ◽  
Mitochondrial Uncoupling ◽  
Knock Out ◽  
Atp Production ◽  
Consumption Rates ◽  
Mitochondrial Efficiency ◽  
Salt Sensitive Hypertension

Hypertension is a complex disease and a leading cause of morbidity and mortality globally. Although oxidative stress and mitochondrial dysfunction have been found in the kidney in various models of hypertension, progressive alteration of mitochondrial oxidative phosphorylation (OxPhos) in the kidney during the development of salt-sensitive hypertension has not been characterized. The present study determined changes of OxPhos in kidneys of Dahl salt-sensitive (SS) rats before (0.4% NaCl diet; LS) and after switching to a high salt diet (4.0% NaCl; HS) during the development of hypertension. Mitochondria were isolated from the outer medulla (OM) and cortex of the kidney of SS rats fed a LS diet since weaning and studied at days 3, 7, 14 & 21 of a HS diet feeding. Oxygen consumption rates (OCR) were measured in mitochondria energized with pyruvate + malate as substrates for three different respiratory states using an Oroboros Oxygraph-2k Instrument. This includes i) leak state (in the absence of ADP), ii) ADP-stimulated state, and iii) uncoupled state (in the presence of an uncoupler FCCP). A biphasic pattern of ADP-stimulated OCR with progressive uncoupling was observed in both the renal OM and cortex. Mitochondrial efficiency for ATP synthesis was increased in the early phases of hypertension (3 & 7 days) but was severely compromised in the established phases of hypertension (14 & 21 days). This decreased mitochondrial efficiency was associated with uncoupling of OxPhos and high levels of oxidative stress which we hypothesized were due to mitochondrial ROS stimulation of membrane NOXs. To test this, experiments were performed in SS rats with double knock out (DKO) of the cytosolic subunit of NOX2 (p67 phox ) and NOX4 (SS p67phox-/-/Nox4-/- ). DKO SS rats were fed a HS diet and OCR of renal cortical and OM mitochondria was determined at days 7 and 14. In contrast to SS rats, the DKO SS rats fed a HS diet showed no significant differences in mitochondrial OCR in the cortex or OM, nor to a control group maintained on a LS diet. HS diet in SS rats initially increases the efficiency of renal cortical and medullary mitochondrial ATP production (days 1-7) followed by an enhanced ROS production with mitochondrial uncoupling and reduced efficiency of ATP production by the third week.

scholarly journals Alterations in Glucose Metabolism During the Transition to Heart Failure: The Contribution of UCP-2

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 552 ◽  
Author(s):  
Hanna Sarah Kutsche ◽  
Rolf Schreckenberg ◽  
Martin Weber ◽  
Christine Hirschhäuser ◽  
Susanne Rohrbach ◽  
...  
Keyword(s):  
Heart Failure ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Contractile Function ◽  
Uncoupling Protein ◽  
Left Ventricular ◽  
Mitochondrial Uncoupling ◽  
Glut 4

The cardiac expression of the mitochondrial uncoupling protein (UCP)-2 is increased in patients with heart failure. However, the underlying causes as well as the possible consequences of these alterations during the transition from hypertrophy to heart failure are still unclear. To investigate the role of UCP-2 mechanistically, expression of UCP-2 was silenced by small interfering RNA in adult rat ventricular cardiomyocytes. We demonstrate that a downregulation of UCP-2 by siRNA in cardiomyocytes preserves contractile function in the presence of angiotensin II. Furthermore, silencing of UCP-2 was associated with an upregulation of glucose transporter type (Glut)-4, increased glucose uptake, and reduced intracellular lactate levels, indicating improvement of the oxidative glucose metabolism. To study this adaptation in vivo, spontaneously hypertensive rats served as a model for cardiac hypertrophy due to pressure overload. During compensatory hypertrophy, we found low UCP-2 levels with an upregulation of Glut-4, while the decompensatory state with impaired function was associated with an increase of UCP-2 and reduced Glut-4 expression. By blocking the aldosterone receptor with spironolactone, both cardiac function as well as UCP-2 and Glut-4 expression levels of the compensated phase could be preserved. Furthermore, we were able to confirm this by left ventricular (LV) biopsies of patients with end-stage heart failure. The results of this study show that UCP-2 seems to impact the cardiac glucose metabolism during the transition from hypertrophy to failure by affecting glucose uptake through Glut-4. We suggest that the failing heart could benefit from low UCP-2 levels by improving the efficiency of glucose oxidation. For this reason, UCP-2 inhibition might be a promising therapeutic strategy to prevent the development of heart failure.

Mitochondrial uncoupling reduces exercise capacity despite several skeletal muscle metabolic adaptations

2014 ◽  
Vol 116 (4) ◽  
pp. 364-375 ◽  
Author(s):  
A. I. Schlagowski ◽  
F. Singh ◽  
A. L. Charles ◽  
T. Gali Ramamoorthy ◽  
F. Favret ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mrna Expression ◽  
Exercise Capacity ◽  
Maximal Exercise ◽  
Mitochondrial Fission ◽  
Critical Factor ◽  
Histochemical Staining ◽  
Running Economy ◽  
Control Group ◽  
Mitochondrial Uncoupling

The effects of mitochondrial uncoupling on skeletal muscle mitochondrial adaptation and maximal exercise capacity are unknown. In this study, rats were divided into a control group (CTL, n = 8) and a group treated with 2,4-dinitrophenol, a mitochondrial uncoupler, for 28 days (DNP, 30 mg·kg−1·day−1in drinking water, n = 8). The DNP group had a significantly lower body mass ( P < 0.05) and a higher resting oxygen uptake (V̇o2, P < 0.005). The incremental treadmill test showed that maximal running speed and running economy ( P < 0.01) were impaired but that maximal V̇o2(V̇o2max) was higher in the DNP-treated rats ( P < 0.05). In skinned gastrocnemius fibers, basal respiration (V0) was higher ( P < 0.01) in the DNP-treated animals, whereas the acceptor control ratio (ACR, Vmax/V0) was significantly lower ( P < 0.05), indicating a reduction in OXPHOS efficiency. In skeletal muscle, DNP activated the mitochondrial biogenesis pathway, as indicated by changes in the mRNA expression of PGC1-α and -β, NRF-1 and −2, and TFAM, and increased the mRNA expression of cytochrome oxidase 1 ( P < 0.01). The expression of two mitochondrial proteins (prohibitin and Ndufs 3) was higher after DNP treatment. Mitochondrial fission 1 protein (Fis-1) was increased in the DNP group ( P < 0.01), but mitofusin-1 and -2 were unchanged. Histochemical staining for NADH dehydrogenase and succinate dehydrogenase activity in the gastrocnemius muscle revealed an increase in the proportion of oxidative fibers after DNP treatment. Our study shows that mitochondrial uncoupling induces several skeletal muscle adaptations, highlighting the role of mitochondrial coupling as a critical factor for maximal exercise capacities. These results emphasize the importance of investigating the qualitative aspects of mitochondrial function in addition to the amount of mitochondria.

Uncoupling protein 3 biological activity

2001 ◽  
Vol 29 (6) ◽  
pp. 774-777 ◽  
Author(s):  
J. P. Giacobino
Keyword(s):  
Biological Activity ◽  
Heat Dissipation ◽  
Ex Vivo ◽  
Uncoupling Protein ◽  
In Vivo Studies ◽  
Muscle Fibre Types ◽  
Uncoupling Protein 3 ◽  
Intronic Polymorphism

The hypothesis that uncoupling protein 3 (UCP3) is an uncoupling protein involved in heat dissipation is not unequivocally supported. An update of in vitro, ex vivo and in vivo studies testing this hypothesis is presented. Data are provided showing that exercise induces a fatty acid-dependent increase in muscle UCP3 mRNA in humans. The proposed positive correlation between glycolytic capacity and UCP3 level in various muscle-fibre types in the mouse is reassessed. Finally, an association between an intronic polymorphism of UCP3 and adiposity is reported.

Effect of Thyroid Hormone on Uncoupling Protein-3 mRNA Expression in Rat Heart and Skeletal Muscle

Thyroid ◽  
2004 ◽  
Vol 14 (3) ◽  
pp. 177-185 ◽  
Author(s):  
Marcia Silva Queiroz ◽  
Yvonne Shao ◽  
Faramarz Ismail-Beigi
Keyword(s):  
Skeletal Muscle ◽  
Thyroid Hormone ◽  
Mrna Expression ◽  
Rat Heart ◽  
Uncoupling Protein ◽  
Uncoupling Protein 3

scholarly journals Identification of a fatty acid-sensitive interaction between mitochondrial uncoupling protein 3 and enoyl-CoA hydratase 1 in skeletal muscle

2019 ◽  
Author(s):  
Christine K. Dao ◽  
Alexander Kenaston ◽  
Katsuya Hirasaka ◽  
Shohei Kohno ◽  
Christopher Riley ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Uncoupling Protein ◽  
Pathophysiological Mechanism ◽  
Mitochondrial Uncoupling ◽  
Skeletal Myocytes ◽  
Mitochondrial Uncoupling Protein ◽  
Uncoupling Protein 3 ◽  
Mitochondrial Fatty Acid ◽  
Metabolizing Enzyme

SummarySkeletal muscle mitochondrial fatty acid (FA) overload in response to chronic overnutrition is a prominent pathophysiological mechanism in obesity-induced metabolic disease. Increased disposal of FAs is therefore an attractive strategy for intervening in obesity and related disorders. Skeletal muscle uncoupling protein 3 (UCP3) activity is associated with increased FA oxidation and antagonizes weight gain in mice on obesogenic diets, but the mechanisms involved are not clear. Here, we show that UCP3 forms a direct, FA-stimulated, mitochondrial matrix-localized complex with the auxiliary unsaturated FA-metabolizing enzyme, Δ3,5-Δ2,4dienoyl-CoA-isomerase (ECH1). Expression studies in C2C12 myoblasts that functionally augments state 4 (uncoupled) respiration and FA oxidation in skeletal myocytes.Mechanistic studies indicate that ECH1:UCP3 complex formation is likely stimulated by FA import into the mitochondria to enhance uncoupled respiration and unsaturated FA oxidation in mouse skeletal myocytes. In order to characterize the contribution of ECH1-dependent FA metabolism in NST, we generated an ECH1 knockout mouse and found that these mice were severely cold intolerant, despite an up-regulation of UCP3 expression in SKM. These findings illuminate a novel mechanism that links unsaturated FA metabolism with mitochondrial uncoupling and non-shivering thermogenesis in SKM.

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