Hypoxanthine Induces Muscular ATP Depletion and Fatigue via UCP2

Hypoxanthine (Hx), an intermediate metabolite of the purine metabolism pathway which is dramatically increased in blood and skeletal muscle during muscle contraction and metabolism, is characterized as a marker of exercise exhaustion. However, the physiological effects of Hx on skeletal muscle remain unknown. Herein, we demonstrate that chronic treatment with Hx through dietary supplementation resulted in skeletal muscle fatigue and impaired the exercise performance of mice without affecting their growth and skeletal muscle development. Hx increased the uncoupling protein 2 (UCP2) expression in the skeletal muscle, which led to decreased energy substrate storage and enhanced glycolysis. These effects could also be verified in acute treatment with Hx through intraperitoneal injection. In addition, muscular specifically knockout of UCP2 through intra-muscle tissue injection of adenovirus-associated virus reversed the effects of Hx. In conclusion, we identified a novel role of Hx in the skeletal muscular fatigue mediated by UCP2-dependent mitochondrial uncoupling. This finding may shed light on the pathological mechanism of clinical muscle dysfunctions due to abnormal metabolism, such as muscle fatigue and weakness.

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Mitochondrial uncoupling protein-2 deficiency protects steatotic mouse hepatocytes from hypoxia/reoxygenation

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00049.2011 ◽

2012 ◽

Vol 302 (3) ◽

pp. G336-G342 ◽

Cited By ~ 10

Author(s):

Zachary P. Evans ◽

Arun P. Palanisamy ◽

Alton G. Sutter ◽

Justin D. Ellett ◽

Venkat K. Ramshesh ◽

...

Keyword(s):

Lipid Peroxidation ◽

Uncoupling Protein ◽

Thiobarbituric Acid ◽

Atp Depletion ◽

Uncoupling Protein 2 ◽

Mitochondrial Uncoupling ◽

Mitochondrial Uncoupling Protein ◽

Ucp2 Expression ◽

Hypoxia Reoxygenation

Steatotic livers are sensitive to ischemic events and associated ATP depletion. Hepatocellular necrosis following these events may result from mitochondrial uncoupling protein-2 (UCP2) expression. To test this hypothesis, we developed a model of in vitro steatosis using primary hepatocytes from wild-type (WT) and UCP2 knockout (KO) mice and subjected them to hypoxia/reoxygenation (H/R). Using cultured hepatocytes treated with emulsified fatty acids for 24 h, generating a steatotic phenotype (i.e., microvesicular and broad-spectrum fatty acid accumulation), we found that the phenotype of the WT and UCP2 KO were the same; however, cellular viability was increased in the steatotic KO hepatocytes following 4 h of hypoxia and 24 h of reoxygenation; Hepatocellular ATP levels decreased during hypoxia and recovered after reoxygenation in the control and UCP2 KO steatotic hepatocytes but not in the WT steatotic hepatocytes; mitochondrial membrane potential in WT and UCP2 KO steatotic groups was less than control groups but higher than UCP2 KO hepatocytes. Following reoxygenation, lipid peroxidation, as measured by thiobarbituric acid reactive substances, increased in all groups but to a greater extent in the steatotic hepatocytes, regardless of UCP2 expression. These results demonstrate that UCP2 sensitizes steatotic hepatocytes to H/R through mitochondrial depolarization and ATP depletion but not lipid peroxidation.

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Dissociation of obesity and insulin resistance in transgenic mice with skeletal muscle expression of uncoupling protein 1

Physiological Genomics ◽

10.1152/physiolgenomics.00194.2007 ◽

2008 ◽

Vol 32 (3) ◽

pp. 352-359 ◽

Cited By ~ 30

Author(s):

Yvonne Katterle ◽

Susanne Keipert ◽

Jana Hof ◽

Susanne Klaus

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Uncoupling Protein ◽

Wild Type ◽

Uncoupling Protein 1 ◽

Mitochondrial Uncoupling ◽

High Fat Diets ◽

Fat Diets ◽

White Fat

We evaluated the effect of skeletal muscle mitochondrial uncoupling on energy and glucose metabolism under different diets. For 3 mo, transgenic HSA-mUCP1 mice with ectopic expression of uncoupling protein 1 in skeletal muscle and wild-type littermates were fed semisynthetic diets with varying macronutrient ratios (energy % carbohydrate-protein-fat): HCLF (41:42:17), HCHF (41:16:43); LCHF (11:45:44). Body composition, energy metabolism, and insulin resistance were assessed by NMR, indirect calorimetry, and insulin tolerance test, respectively. Gene expression in different organs was determined by real-time PCR. In wild type, both high-fat diets led to an increase in body weight and fat. HSA-mUCP1 mice considerably increased body fat on HCHF but stayed lean on the other diets. Irrespective of differences in body fat content, HSA-mUCP1 mice showed higher insulin sensitivity and decreased plasma insulin and liver triglycerides. Respiratory quotient and gene expression indicated overall increased carbohydrate oxidation of HSA-mUCP1 but a preferential channeling of fatty acids into muscle rather than liver with high-fat diets. Evidence for increased lipogenesis in white fat of HSA-mUCP1 mice suggests increased energy dissipating substrate cycling. Retinol binding protein 4 expression in white fat was increased in HSA-mUCP1 mice despite increased insulin sensitivity, excluding a causal role in the development of insulin resistance. We conclude that skeletal muscle mitochondrial uncoupling does not protect from the development of obesity in all circumstances. Rather it can lead to a “healthy” obese phenotype by preserving insulin sensitivity and a high metabolic flexibility, thus protecting from the development of obesity associated disturbances of glucose homeostasis.

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

Archives of Biochemistry and Biophysics ◽

10.1016/j.abb.2019.01.018 ◽

2019 ◽

Vol 663 ◽

pp. 239-248 ◽

Cited By ~ 7

Author(s):

S. McBride ◽

L. Wei-LaPierre ◽

F. McMurray ◽

M. MacFarlane ◽

X. Qiu ◽

...

Keyword(s):

Skeletal Muscle ◽

Uncoupling Protein ◽

Uncoupling Protein 3

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Mitochondrial Uncoupling Proteins in Mammals and Plants

Bioscience Reports ◽

10.1023/a:1013604526175 ◽

2001 ◽

Vol 21 (2) ◽

pp. 201-212 ◽

Cited By ~ 44

Author(s):

Jirí Borecký ◽

Ivan G. Maia ◽

Paulo Arruda

Keyword(s):

Uncoupling Protein ◽

Uncoupling Proteins ◽

Mitochondrial Uncoupling ◽

Anion Transporter ◽

Distinct Cluster ◽

Mitochondrial Uncoupling Proteins ◽

Shivering Thermogenesis ◽

General Balance ◽

Anion Carrier

Uncoupling proteins (UCPs) belong to a distinct cluster of the mitochondrial anion carrier family. Up to five different uncoupling protein types were found in mitochondria of mammals and plants, and recently in fishes, fungi and protozoa. They exhibit a significantly conserved structure with several motifs specific to either the whole cluster or protein type. Uncoupling proteins, as well as the whole mitochondrial anion carrier gene family, probably emerged in evolution before the separation of animal, fungi, and plant kingdoms and originate from an anion/nucleotide or anion/anion transporter ancestor. Mammalian UCP1, UCP2, UCP3, and plant uncoupling proteins pUCP1 and pUCP2 are similar and seem to form one subgroup, whereas UCP4 and BMCP1 belong to a different group. Molecular, biochemical, and phylogenic data suggest that UCP2 could be considered as an UCP-prototype. UCP1 plays its biological role mainly in the non-shivering thermogenesis while the role of the other types is unknown. However, hypotheses have suggested that they are involved in the general balance of basic energy expenditure, protection from reactive oxygen species, and, in plants, in fruit ripening and seed ontogeny.

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Mitochondrial uncoupling protein 3 (UCP3) in skeletal muscle

Frontiers in Bioscience ◽

10.2741/kasaoka ◽

2001 ◽

Vol 6 (1) ◽

pp. d570 ◽

Cited By ~ 2

Author(s):

Nobuyo Tsuboyama-Kasaoka

Keyword(s):

Skeletal Muscle ◽

Uncoupling Protein ◽

Mitochondrial Uncoupling ◽

Mitochondrial Uncoupling Protein ◽

Uncoupling Protein 3

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Neuroprotective Role of Mitochondrial Uncoupling Protein 2 in Cerebral Stroke

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2009.4 ◽

2009 ◽

Vol 29 (6) ◽

pp. 1069-1078 ◽

Cited By ~ 49

Author(s):

Suresh L Mehta ◽

P. Andy Li

Keyword(s):

Uncoupling Protein ◽

Cellular Damage ◽

Cerebral Stroke ◽

Inner Mitochondrial Membrane ◽

Mitochondrial Uncoupling ◽

Mitochondria Membrane Potential ◽

Mitochondrial Uncoupling Protein ◽

Mitochondrial Transporter ◽

Develop Strategy

The uncoupling proteins (UCPs) are mitochondrial transporter proteins involved in proton conductance across inner mitochondrial membrane (IMM). UCP2, which is one of the members of this class of proteins, has a wide but restricted tissue distribution including brain. Its physiologic role according to emerging evidences, although still not clear, indicate that distribution of UCP2 may be related to regulation of mitochondria membrane potential (ΔΨm), production of reactive oxygen species (ROS), preservation of calcium homeostasis, modulation of neuronal activity, and eventually inhibition of cellular damage. These factors are very important in determining the fate of neurons and damage progression in the brain during various neurodegenerative diseases including cerebral stroke. Recent evidence indicates that an increased expression and activity of UCP2 are well correlated with neuronal survival after stroke and trauma. This review briefly covers the present understanding of UCP2, which eventually may be beneficial to understand the precise role of UCP2 to develop strategy to identify its potential therapeutic application.

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Transforming growth factor-β and myostatin signaling in skeletal muscle

Journal of Applied Physiology ◽

10.1152/japplphysiol.01091.2007 ◽

2008 ◽

Vol 104 (3) ◽

pp. 579-587 ◽

Cited By ~ 182

Author(s):

Helen D. Kollias ◽

John C. McDermott

Keyword(s):

Skeletal Muscle ◽

Growth Factor ◽

Signaling Pathway ◽

Muscle Development ◽

Cellular Proliferation ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Related Family ◽

Cytokine Milieu

The superfamily of transforming growth factor-β (TGF-β) cytokines has been shown to have profound effects on cellular proliferation, differentiation, and growth. Recently, there have been major advances in our understanding of the signaling pathway(s) conveying TGF-β signals to the nucleus to ultimately control gene expression. One tissue that is potently influenced by TGF-β superfamily signaling is skeletal muscle. Skeletal muscle ontogeny and postnatal physiology have proven to be exquisitely sensitive to the TGF-β superfamily cytokine milieu in various animal systems from mice to humans. Recently, major strides have been made in understanding the role of TGF-β and its closely related family member, myostatin, in these processes. In this overview, we will review recent advances in our understanding of the TGF-β and myostatin signaling pathways and, in particular, focus on the implications of this signaling pathway for skeletal muscle development, physiology, and pathology.

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