In Vivo Effects of Uncoupling Protein-3 Gene Disruption on Mitochondrial Energy Metabolism

Cline, Gary W.; Vidal-Puig, António; Dufour, Sylvie; Cadman, Kevin S.; Lowell, Bradford B.; Shulman, Gerald I.

doi:10.1074/jbc.m102540200

Cited by 133 publications

(138 citation statements)

References 16 publications

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“…Experiments conducted in UCP3 knockout mice have actually not illustrated a major involvement of UCP3 in the regulation of whole-body energy metabolism. [14][15][16] These genetically modified mice did not show changes in body mass and their metabolic rates were similar to those measured in the wild-type animals. Alternatively, on the basis of the present results, we hypothesize that UCP3 is involved in the control of ATP production in skeletal muscle at rest and during muscle activity.…”

Section: Discussionsupporting

confidence: 60%

Capsiate administration results in an uncoupling protein-3 downregulation, an enhanced muscle oxidative capacity and a decreased abdominal fat content in vivo

et al. 2009

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Objectives: The involvement of skeletal muscle mitochondrial uncoupling protein-3 (UCP3) in the control of energy expenditure in skeletal muscle and at the whole-body level is still a matter of debate. We previously reported that UCP3 downregulation is linked to an enhanced mitochondrial energy metabolism in rat skeletal muscle as a result of acute capsiate treatment. Here, we aimed at investigating noninvasively the effects of chronic capsiate ingestion on metabolic changes occurring in exercising gastrocnemius muscle and at the whole-body level. Methods: We used an original experimental setup allowing a complete noninvasive investigation of gastrocnemius muscle function in situ using 31-phosphorus magnetic resonance spectroscopy. Whole-body fat composition was determined using magnetic resonance imaging and UCP3 gene expression was measured by quantitative real-time RT-PCR analysis. Results: We found that a 14-day daily administration of capsiate (100 mg kg À1 body weight) reduced UCP3 gene expression and increased phosphocreatine level at baseline and during the stimulation period in gastrocnemius muscle. During muscle stimulation, pH i showed a larger alkalosis in the capsiate group suggesting a lower glycolysis and a compensatory higher aerobic contribution to ATP production. Although the capsiate-treated rats were hyperphagic as compared to control animals, they showed a lower weight gain coupled to a decreased abdominal fat content. Conclusion: Overall, our data indicated that capsiate administration contributes to the enhancement of aerobic ATP production and the reduction of body fat content coupled to a UCP3 gene downregulation.

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Section: Discussionsupporting

confidence: 60%

Capsiate administration results in an uncoupling protein-3 downregulation, an enhanced muscle oxidative capacity and a decreased abdominal fat content in vivo

et al. 2009

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“…The results of two studies on UCP3 knockout mice were interpreted to indicate that mitochondria were more tightly coupled, with an increased state 3-to-state 4 ratio in one study (34) and, in another study (9), a fourfold increase in the rate of ATP synthesis with no change in citrate cycle flux, CO 2 production, or energy expenditure. The latter finding is surprising, because the theoretical maximum P/O ratio (i.e., number of ATPs generated per oxygen atom) is 3, whereas more recently values of ϳ2.5 have been obtained (3).…”

Section: Discussionmentioning

confidence: 99%

“…UCP1 mediates adaptive thermogenesis in brown adipose tissue by uncoupling mitochondrial respiration from ATP synthesis (27). Because UCP3 is a homolog of UCP1, it has been proposed that UCP3 also functions as an uncoupling protein that plays a role in skeletal muscle thermogenesis and energy expenditure (6,9,14,20).…”

Section: Discussionmentioning

confidence: 99%

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Exercise induces an increase in muscle UCP3 as a component of the increase in mitochondrial biogenesis

Jones

Baar

Ojuka

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

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Previous studies have indicated that exercise acutely induces large increases in uncoupling protein-3 (UCP3) in skeletal muscle, whereas endurance training results in marked decreases in muscle UCP3. Because UCP3 expression appears to be regulated by the same mechanism as other mitochondrial constituents, it seemed unlikely that exercise would result in such large and divergent changes in mitochondrial composition. The purpose of this study was to test the hypothesis that major changes in UCP3 protein concentration do not occur independently of mitochondrial biogenesis and that UCP3 increases as a component of the exercise-induced increase in mitochondria. We found a large increase in UCP3 mRNA immediately and 3 h after a bout of swimming. UCP3 protein concentration was increased ϳ35% 18 h after a single exercise bout, ϳ63% after 3 days, and ϳ84% after 10 days of exercise. These increases in UCP3 roughly paralleled those of other mitochondrial marker proteins. Our results are consistent with the interpretation that endurance exercise induces an adaptive increase in mitochondria that have a normal content of UCP3. gene expression; cytochrome c; cytochrome oxidase; skeletal muscle THE MITCHONDRIAL PROTEIN UCP3 was identified on the basis of its homology with the uncoupling protein-1 (UCP1) present in brown adipose tissue (14). It has been proposed on the basis of its homology with UCP1 that UCP3 also functions as an uncoupling protein (5, 14). Furthermore, some investigators have interpreted the results of studies of the heterologous expression of UCP3 in yeast (36) and of overexpression or knockout of UCP3 in transgenic mice (8, 9, 34) as providing evidence for uncoupling.UCP3 is expressed primarily in skeletal muscle (14). Because of its possible role in energy metabolism, a number of investigators have studied the adaptive response of UCP3 in skeletal muscle to exercise (11,23,29,33,37). reported that UCP3 mRNA was increased sevenfold in skeletal muscle of mice 3 h after a single bout of treadmill running and 16-fold 3 h after exercise in mice that had been trained for 3 wk by swimming. They speculated that "upregulation of UCP3 mRNA may be a defense mechanism against extra energy supply to consume extra energy in skeletal muscle." Similarly, Zhou et al. (37) reported that UCP3 mRNA was increased approximately sevenfold immediately after a 200-min-long bout of swimming. A similar response was seen after a bout of treadmill running. They also reported that UCP3 protein concentration was increased 3.5-fold immediately after 100 min of treadmill running and 5.6-fold immediately after 200 min of running (37). In studies in humans, Pilegaard et al. (23) found an ϳ2.5-fold increase in UCP3 mRNA 4 h after a 4-h bout of cycling, and Schrauwen et al. (29) reported an approximately twofold increase in UCP3 mRNA 4 h after exercise in men who performed cycle exercise for 2 h in the fasting state.Although there were differences in the time course and magnitudes of the increases, all of the studies on the acute effect of ex...

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“…This was compared with P i magnetization in the absence of γ-ATP saturation (M 0 Pi ). T1′ Pi , the spin lattice relaxation time for P i in the presence of γ-ATP saturation measured in an earlier study (Cline et al 2001), was used here…”

Section: P Mr Spectroscopymentioning

confidence: 99%

Skeletal muscle ATP kinetics are impaired in frail mice

Akki

Yang

Gupta

et al. 2013

AGE

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The interleukin-10 knockout mouse (IL10 tm/tm ) has been proposed as a model for human frailty, a geriatric syndrome characterized by skeletal muscle (SM) weakness, because it develops an age-related decline in SM strength compared to control (C57BL/6J) mice. Compromised energy metabolism and energy deprivation appear to play a central role in muscle weakness in metabolic myopathies and muscular dystrophies. Nonetheless, it is not known whether SM energy metabolism is altered in frailty. A combination of in vivo 31 P nuclear magnetic resonance experiments and biochemical assays was used to measure high-energy phosphate concentrations, the rate of ATP synthesis via creatine kinase (CK), the primary energy reserve reaction in SM, as well as the unidirectional rates of ATP synthesis from inorganic phosphate (P i ) in hind limb SM of 92-week-old control (n=7) and IL10 tm/tm (n=6) mice. SM Phosphocreatine (20.2±2.3 vs. 16.8± 2.3 μmol/g, control vs. IL10 tm/tm , p<0.05), ATP flux via CK (5.0±0.9 vs. 3.1±1.1 μmol/g/s, p<0.01), ATP synthesis from inorganic phosphate (P i →ATP) (0.58±0.3 vs. 0.26±0.2 μmol/g/s, p<0.05) and the free energy released from ATP hydrolysis (ΔG ∼ATP ) were significantly lower and [P i ] (2.8±1.0 vs. 5.3± 2.0 μmol/g, control vs. IL10 tm/tm , p<0.05) markedly higher in IL10 tm/tm than in control mice. These observations demonstrate that, despite normal in vitro metabolic enzyme activities, in vivo SM ATP kinetics, high-energy phosphate levels and energy release from ATP hydrolysis are reduced and inorganic phosphate is elevated in a murine model of frailty. These observations do not prove, but are consistent with the premise, that energetic abnormalities may contribute metabolically to SM weakness in this geriatric syndrome.

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In Vivo Effects of Uncoupling Protein-3 Gene Disruption on Mitochondrial Energy Metabolism

Cited by 133 publications

References 16 publications

Capsiate administration results in an uncoupling protein-3 downregulation, an enhanced muscle oxidative capacity and a decreased abdominal fat content in vivo

Capsiate administration results in an uncoupling protein-3 downregulation, an enhanced muscle oxidative capacity and a decreased abdominal fat content in vivo

Exercise induces an increase in muscle UCP3 as a component of the increase in mitochondrial biogenesis

Skeletal muscle ATP kinetics are impaired in frail mice

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