Role of UCP3 in state 4 respiration during contractile activity-induced mitochondrial biogenesis

2004 ◽  
Vol 97 (3) ◽  
pp. 976-983 ◽  
Author(s):  
Vladimir Ljubicic ◽  
Peter J. Adhihetty ◽  
David A. Hood
Keyword(s):  
Skeletal Muscle ◽  
Protein Expression ◽  
Mitochondrial Biogenesis ◽  
Contractile Activity ◽  
Uncoupling Protein ◽  
Uncoupling Protein 3 ◽  
Chronic Electrical Stimulation ◽  
The Relationship ◽  
The Imf

In an effort to better characterize uncoupling protein-3 (UCP3) function in skeletal muscle, we assessed basal UCP3 protein content in rat intermyofibrillar (IMF) and subsarcolemmal (SS) mitochondrial subfractions in conjunction with measurements of state 4 respiration. UCP3 content was 1.3-fold ( P < 0.05) greater in IMF compared with SS mitochondria. State 4 respiration was 2.6-fold greater ( P < 0.05) in the IMF subfraction than in SS mitochondria. GDP attenuated state 4 respiration by ∼40% ( P < 0.05) in both subfractions. The UCP3 activator oleic acid (OA) significantly increased state 4 respiration in IMF mitochondria only. We used chronic electrical stimulation (3 h/day for 7 days) to investigate the relationship between changes in UCP3 protein expression and alterations in state 4 respiration during contractile activity-induced mitochondrial biogenesis. UCP3 content was increased by 1.9- and 2.3-fold in IMF and SS mitochondria, respectively, which exceeded the concurrent 40% ( P < 0.05) increase in cytochrome- c oxidase activity. Chronic contractile activity increased state 4 respiration by 1.4-fold ( P < 0.05) in IMF mitochondria, but no effect was observed in the SS subfraction. The uncoupling function of UCP3 accounted for 50–57% of the OA-induced increase in state 4 respiration in IMF mitochondria, which was independent of the induced twofold difference in UCP3 content due to chronic contractile activity. Thus modifications in UCP3 function are more important than changes in UCP3 expression in modifying state 4 respiration. This effect is evident in IMF but not SS mitochondria. We conclude that UCP3 at physiological concentrations accounts for a significant portion of state 4 respiration in both IMF and SS mitochondria, with the contribution being greater in the IMF subfraction. In addition, the contradiction between human and rat training studies with respect to UCP3 protein expression may partly be explained by the greater than twofold difference in mitochondrial UCP3 content between rat and human skeletal muscle.

scholarly journals Skeletal muscle mitoflashes, pH, and the role of uncoupling protein-3

2019 ◽  
Vol 663 ◽  
pp. 239-248 ◽  
Author(s):  
S. McBride ◽  
L. Wei-LaPierre ◽  
F. McMurray ◽  
M. MacFarlane ◽  
X. Qiu ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Uncoupling Protein ◽  
Uncoupling Protein 3

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

2003 ◽  
Vol 284 (1) ◽  
pp. E96-E101 ◽  
Author(s):  
Terry E. Jones ◽  
Keith Baar ◽  
Edward Ojuka ◽  
May Chen ◽  
John O. Holloszy
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Biogenesis ◽  
Protein Concentration ◽  
Uncoupling Protein ◽  
Exercise Bout ◽  
Mitochondrial Marker ◽  
Marker Proteins ◽  
Uncoupling Protein 3 ◽  
Exercise Induced ◽  
Ucp3 Expression

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 ∼35% 18 h after a single exercise bout, ∼63% after 3 days, and ∼84% 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.

scholarly journals Expression of uncoupling protein 3 is upregulated in skeletal muscle during sepsis

2003 ◽  
Vol 285 (3) ◽  
pp. E512-E520 ◽  
Author(s):  
Xiaoyan Sun ◽  
Curtis Wray ◽  
Xintian Tian ◽  
Per-Olof Hasselgren ◽  
James Lu
Keyword(s):  
Skeletal Muscle ◽  
Protein Expression ◽  
Ex Vivo ◽  
Uncoupling Protein ◽  
Cecal Ligation ◽  
Skeletal Muscle Atrophy ◽  
Protein Levels ◽  
Mitochondrial Transporter ◽  
Uncoupling Protein 3 ◽  
Gene And Protein Expression

Uncoupling protein 3 (UCP3) is a member of the mitochondrial transporter superfamily that is expressed primarily in skeletal muscle. UCP3 is upregulated in various conditions characterized by skeletal muscle atrophy, including hyperthyroidism, fasting, denervation, diabetes, cancer, lipopolysaccharide (LPS), and treatment with glucocorticoids (GCs). The influence of sepsis, another condition characterized by muscle cachexia, on UCP3 expression and activity is not known. We examined UCP3 gene and protein expression in skeletal muscles from rats after cecal ligation and puncture and from sham-operated control rats. Sepsis resulted in a two- to threefold increase in both mRNA and protein levels of UCP3 in skeletal muscle. Treatment of rats with the glucocorticoid receptor antagonist RU-38486 prevented the sepsis-induced increase in gene and protein expression of UCP3. The UCP3 mRNA and protein levels were increased 2.4- to 3.6-fold when incubated muscles from normal rats were treated with dexamethasone (DEX) and/or free fatty acids (FFA ) ex vivo. In addition, UCP3 mRNA and protein levels were significantly increased in normal rat muscles in vivo with treatment of either DEX or FFA. The results suggest that sepsis upregulates the gene and protein expression of UCP3 in skeletal muscle, which may at least in part be mediated by GCs and FFA.

Curcumin induces mitochondrial biogenesis by increasing cAMP levels via PDE4A inhibition in skeletal muscle

2021 ◽  
pp. 1-34
Author(s):  
Hamidie Ronald D Ray ◽  
Tsubasa Shibaguchi ◽  
Tatsuya Yamada ◽  
Rikuhide Koma ◽  
Rie Ishizawa ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Expression ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Respiration ◽  
Citrate Synthase ◽  
Signalling Pathway ◽  
Curcumin Treatment ◽  
Camp Content ◽  
Signalling Molecules ◽  
Camp Levels

Abstract Background: Previous research has suggested that curcumin potentially induces mitochondrial biogenesis in skeletal muscle via increasing cAMP levels. However, the regulatory mechanisms for this phenomenon remain unknown. The purpose of the present study was to clarify the mechanism by which curcumin activates cAMP-related signalling pathways that upregulate mitochondrial biogenesis and respiration in skeletal muscle. Methods: The effect of curcumin treatment (i.p., 100 mg/kg-BW/day for 28 days) on mitochondrial biogenesis was determined in rats. The effects of curcumin and exercise (swimming for 2 h/day for 3 days) on the cAMP signalling pathway were determined in the absence and presence of phosphodiesterase (PDE) or protein kinase A (PKA) inhibitors. Mitochondrial respiration, citrate synthase (CS) activity, cAMP content, and protein expression of cAMP/PKA signalling molecules were analysed. Results: Curcumin administration increased COX-IV protein expression, and CS and complex I activity, consistent with the induction of mitochondrial biogenesis by curcumin. Mitochondrial respiration was not altered by curcumin treatment. Curcumin and PDE inhibition tended to increase cAMP levels with or without exercise. In addition, exercise increased the phosphorylation of PDE4A, whereas curcumin treatment strongly inhibited PDE4A phosphorylation regardless of exercise. Furthermore, curcumin promoted AMPK phosphorylation and PGC-1α deacetylation. Inhibition of PKA abolished the phosphorylation of AMPK. Conclusion: The present results suggest that curcumin increases cAMP levels via inhibition of PDE4A phosphorylation, which induces mitochondrial biogenesis through a cAMP/PKA/AMPK signalling pathway. Our data also suggest the possibility that curcumin utilizes a regulatory mechanism for mitochondrial biogenesis that is distinct from the exercise-induced mechanism in skeletal muscle.

scholarly journals Expression of Uncoupling Protein 3 and GLUT4 Gene in Skeletal Muscle of Preterm Newborns: Possible Control by AMP-Activated Protein Kinase

2006 ◽  
Vol 60 (5) ◽  
pp. 569-575 ◽  
Author(s):  
Petr Brauner ◽  
Pavel Kopecky ◽  
Pavel Flachs ◽  
Ondrej Kuda ◽  
Jaroslav Vorlicek ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Uncoupling Protein ◽  
Uncoupling Protein 3 ◽  
Amp Activated Protein Kinase ◽  
Preterm Newborns

Selected Contribution: Effects of contractile activity on mitochondrial transcription factor A expression in skeletal muscle

2001 ◽  
Vol 90 (1) ◽  
pp. 389-396 ◽  
Author(s):  
Joe W. Gordon ◽  
Arne A. Rungi ◽  
Hidetoshi Inagaki ◽  
David A. Hood
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factor ◽  
Mitochondrial Biogenesis ◽  
Contractile Activity ◽  
Regulatory Protein ◽  
Mrna Levels ◽  
Mitochondrial Transcription ◽  
Mitochondrial Transcription Factor ◽  
Mitochondrial Transcription Factor A ◽  
Mitochondrial Transcript

Mitochondrial transcription factor A (Tfam) is a nuclear-encoded gene product that is imported into mitochondria and is required for the transcription of mitochondrial DNA (mtDNA). We hypothesized that conditions known to produce mitochondrial biogenesis in skeletal muscle would be preceded by an increase in Tfam expression. Therefore, rat muscle was stimulated (10 Hz, 3 h/day). Tfam mRNA levels were significantly elevated (by 55%) at 4 days and returned to control levels at 14 days. Tfam import into intermyofibrillar (IMF) mitochondria was increased by 52 and 61% ( P < 0.05) at 5 and 7 days, respectively. This corresponded to an increase in the level of import machinery components. Immunoblotting data indicated that IMF Tfam protein content was increased by 63% ( P < 0.05) at 7 days of stimulation. This was associated with a 49% ( P < 0.05) increase in complex formation at the mtDNA promoter and a 65% ( P< 0.05) increase in the levels of a mitochondrial transcript, cytochrome- c oxidase (COX) subunit III. Similarly, COX enzyme activity was elevated by 71% ( P < 0.05) after 7 days of contractile activity. These results indicate that early events in mitochondrial biogenesis include increases in Tfam mRNA, followed by accelerations in mitochondrial import and increased Tfam content, which correspond with increased binding to the mtDNA promoter region. This was accompanied by increased mitochondrial transcript levels and elevated COX activity. These data support the role of Tfam as a regulatory protein involved in contractile activity-induced mitochondrial biogenesis.

Abstract 112: A Pathological Role of Endothelial p53 in the Regulation of Endothelial Function and Glucose Metabolism

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Masataka YOKOYAMA ◽  
Yoshio KOBAYASHI ◽  
Tohru MINAMINO
Keyword(s):  
Skeletal Muscle ◽  
Endothelial Cell ◽  
Glucose Metabolism ◽  
Endothelial Function ◽  
Mitochondrial Biogenesis ◽  
Glucose Transporter ◽  
Diabetic Patients ◽  
Glucose Transporter 1 ◽  
P53 Activation

Cellular senescence is a state of irreversible growth arrest induced by various stresses such as oncogenic stimuli. This response is controlled by negative regulators of the cell cycle like the p53 tumor suppressor protein. Accumulating evidence has suggested a role of p53 activation in various age-associated conditions including atherosclerosis, heart failure and diabetes. Here we show that endothelial p53 activation plays a pathological role in the regulation of endothelial function and glucose metabolism under diabetic conditions. Endothelial expression of p53 was markedly up-regulated in a streptozotocin-induced diabetes model. Endothelial function such as acetylcholine-dependent vasodilatation was markedly impaired in this model. Although hyperglycemia was not altered, impairment of endothelial function was significantly improved in mice with endothelial cell-specific p53 deficiency. In same way, p53 was markedly activated in ischemic vessels, and endothelial p53 deficiency enhanced ischemia-induced angiogenesis. Mechanistically, endothelial p53 up-regulated the expression of PTEN that negatively regulated the Akt-eNOS pathway, and therefore disruption of p53 improved endothelial dysfunction. We also found that endothelial p53 was markedly activated, and the Akt-eNOS pathway was attenuated in a diet-induced obesity model. Disruption of endothelial p53 activation improved dietary inactivation of eNOS that up-regulated the expression of PGC-1α in skeletal muscle, thereby increasing mitochondrial biogenesis and oxygen consumption. Inhibition of endothelial p53 also improved dietary impairment of glucose transport into skeletal muscle by up-regulating endothelial expression of glucose transporter 1. Consequently, mice with endothelial cell-specific p53 deficiency fed a high-calorie diet showed improvement of insulin sensitivity and less fat accumulation compared with control littermates. These results indicate that endothelial p53 negatively regulates endothelium-dependent vasodilatation, ischemia-induced angiogenesis, and mitochondrial biogenesis by inhibiting the Akt-eNOS pathway and suggest that inhibition of endothelial p53 could be a novel therapeutic target in diabetic patients.

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