Overexpression of the Cytosolic Form of Phosphoenolpyruvate Carboxykinase (GTP) in Skeletal Muscle Repatterns Energy Metabolism in the Mouse

Transient receptor potential channel V4 (TRPV4) functions as a nonselective cation channel in various cells and plays physiological roles in osmotic and thermal sensation. However, the function of TRPV4 in energy metabolism is unknown. Here, we report that TRPV4 deficiency results in increased muscle oxidative capacity and resistance to diet-induced obesity in mice. Although no difference in body weight was observed between wild-type and Trpv4−/− mice when fed a standard chow diet, obesity phenotypes induced by a high-fat diet were significantly improved in Trpv4−/− mice, without any change in food intake. Quantitative analysis of mRNA revealed the constitutive upregulation of many genes, including those for transcription factors such as peroxisome proliferator-activated receptor α and for metabolic enzymes such as phosphoenolpyruvate carboxykinase. These upregulated genes were especially prominent in oxidative skeletal muscle, in which the activity of Ca2+-dependent phosphatase calcineurin was elevated, suggesting that other Ca2+ channels function in the skeletal muscle of Trpv4−/− mice. Indeed, gene expressions for TRPC3 and TRPC6 increased in the muscles of Trpv4−/− mice compared with those of wild-type mice. The number of oxidative type I fiber also increased in the mutant muscles following myogenin gene induction. These results strongly suggested that inactivation of Trpv4 induces compensatory increases in TRPC3 and TRPC6 production, and elevation of calcineurin activity, affecting energy metabolism through increased expression of genes involved in fuel oxidation in skeletal muscle and thereby contributing to increased energy expenditure and protection from diet-induced obesity in mice.

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Mechanisms of ageing metabolic decline revealed by targeted metabolomics and energy metabolism in NAD+ depleted skeletal muscle

Endocrine Abstracts ◽

10.1530/endoabs.44.p189 ◽

2016 ◽

Author(s):

Rachel Fletcher ◽

Lucy Oldacre-Bartley ◽

Craig Doig ◽

Charles Brenner ◽

Gareth Lavery

Keyword(s):

Skeletal Muscle ◽

Energy Metabolism ◽

Targeted Metabolomics

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Systemic oxidative stress is associated with lower aerobic capacity and impaired skeletal muscle energy metabolism in heart failure patients

Scientific Reports ◽

10.1038/s41598-021-81736-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Takashi Yokota ◽

Shintaro Kinugawa ◽

Kagami Hirabayashi ◽

Mayumi Yamato ◽

Shingo Takada ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Skeletal Muscle ◽

Energy Metabolism ◽

Aerobic Capacity ◽

Plantar Flexion ◽

Exercise Intolerance ◽

Whole Body ◽

Resonance Spectroscopy ◽

Systemic Oxidative Stress

AbstractOxidative stress plays a role in the progression of chronic heart failure (CHF). We investigated whether systemic oxidative stress is linked to exercise intolerance and skeletal muscle abnormalities in patients with CHF. We recruited 30 males: 17 CHF patients, 13 healthy controls. All participants underwent blood testing, cardiopulmonary exercise testing, and magnetic resonance spectroscopy (MRS). The serum thiobarbituric acid reactive substances (TBARS; lipid peroxides) were significantly higher (5.1 ± 1.1 vs. 3.4 ± 0.7 μmol/L, p < 0.01) and the serum activities of superoxide dismutase (SOD), an antioxidant, were significantly lower (9.2 ± 7.1 vs. 29.4 ± 9.7 units/L, p < 0.01) in the CHF cohort versus the controls. The oxygen uptake (VO2) at both peak exercise and anaerobic threshold was significantly depressed in the CHF patients; the parameters of aerobic capacity were inversely correlated with serum TBARS and positively correlated with serum SOD activity. The phosphocreatine loss during plantar-flexion exercise and intramyocellular lipid content in the participants' leg muscle measured by 31phosphorus- and 1proton-MRS, respectively, were significantly elevated in the CHF patients, indicating abnormal intramuscular energy metabolism. Notably, the skeletal muscle abnormalities were related to the enhanced systemic oxidative stress. Our analyses revealed that systemic oxidative stress is related to lowered whole-body aerobic capacity and skeletal muscle dysfunction in CHF patients.

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Enhancement of porcine intramuscular fat content by overexpression of the cytosolic form of phosphoenolpyruvate carboxykinase in skeletal muscle

Scientific Reports ◽

10.1038/srep43746 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 4

Author(s):

Zijian Ren ◽

Ying Wang ◽

Yuanyuan Ren ◽

Zhengwei Zhang ◽

Weiwang Gu ◽

...

Keyword(s):

Skeletal Muscle ◽

Phosphoenolpyruvate Carboxykinase ◽

Intramuscular Fat ◽

Fat Content ◽

Intramuscular Fat Content

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Lack of skeletal muscle IL-6 influences hepatic glucose metabolism in mice during prolonged exercise

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00373.2016 ◽

2017 ◽

Vol 312 (4) ◽

pp. R626-R636 ◽

Cited By ~ 5

Author(s):

Lærke Bertholdt ◽

Anders Gudiksen ◽

Camilla L. Schwartz ◽

Jakob G. Knudsen ◽

Henriette Pilegaard

Keyword(s):

Skeletal Muscle ◽

Glucose Metabolism ◽

Phosphoenolpyruvate Carboxykinase ◽

Prolonged Exercise ◽

Hepatic Glycogen ◽

Glucose Content ◽

Hepatic Glucose Metabolism ◽

Hepatic Glucose ◽

Single Bout ◽

Substrate Choice

The liver is essential in maintaining and regulating glucose homeostasis during prolonged exercise. IL-6 has been shown to be secreted from skeletal muscle during exercise and has been suggested to signal to the liver. Therefore, the aim of this study was to investigate the role of skeletal muscle IL-6 on hepatic glucose regulation and substrate choice during prolonged exercise. Skeletal muscle-specific IL-6 knockout (IL-6 MKO) mice (age, 12–14 wk) and littermate lox/lox (Control) mice were either rested (Rest) or completed a single bout of exercise for 10, 60, or 120 min, and the liver was quickly obtained. Hepatic IL-6 mRNA was higher at 60 min of exercise, and hepatic signal transducer and activator of transcription 3 was higher at 120 min of exercise than at rest in both genotypes. Hepatic glycogen was higher in IL-6 MKO mice than control mice at rest, but decreased similarly during exercise in the two genotypes, and hepatic glucose content was lower in IL-6 MKO than control mice at 120 min of exercise. Hepatic phosphoenolpyruvate carboxykinase mRNA and protein increased in both genotypes at 120 min of exercise, whereas hepatic glucose 6 phosphatase protein remained unchanged. Furthermore, IL-6 MKO mice had higher hepatic pyruvate dehydrogenase (PDH)Ser232 and PDHSer300 phosphorylation than control mice at rest. In conclusion, hepatic gluconeogenic capacity in mice is increased during prolonged exercise independent of muscle IL-6. Furthermore, Skeletal muscle IL-6 influences hepatic substrate regulation at rest and hepatic glucose metabolism during prolonged exercise, seemingly independent of IL-6 signaling in the liver.

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The effect of short-term fasting on liver and skeletal muscle lipid, glucose, and energy metabolism in healthy women and men

The Journal of Lipid Research ◽

10.1194/jlr.p020867 ◽

2011 ◽

Vol 53 (3) ◽

pp. 577-586 ◽

Cited By ~ 44

Author(s):

Jeffrey D. Browning ◽

Jeannie Baxter ◽

Santhosh Satapati ◽

Shawn C. Burgess

Keyword(s):

Skeletal Muscle ◽

Energy Metabolism ◽

Short Term ◽

Muscle Lipid ◽

Healthy Women ◽

Skeletal Muscle Lipid

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Enzyme activities of energy metabolism in skeletal muscle, and in the uterus, during late pregnancy in the mouse

Acta Physiologica Scandinavica ◽

10.1111/j.1748-1716.1984.tb00138.x ◽

1984 ◽

Vol 120 (2) ◽

pp. 305-310 ◽

Cited By ~ 1

Author(s):

JAN ÖRLANDER

Keyword(s):

Skeletal Muscle ◽

Energy Metabolism ◽

Enzyme Activities ◽

Late Pregnancy

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Substrate oxidation in primary human skeletal muscle cells is influenced by donor age

Cell and Tissue Research ◽

10.1007/s00441-020-03275-w ◽

2020 ◽

Vol 382 (3) ◽

pp. 599-608

Author(s):

Vigdis Aas ◽

G. Hege Thoresen ◽

Arild C. Rustan ◽

Jenny Lund

Keyword(s):

Skeletal Muscle ◽

Oleic Acid ◽

Energy Metabolism ◽

Substrate Oxidation ◽

Pyruvate Dehydrogenase Kinase ◽

Acid Oxidation ◽

Acid Uptake ◽

Donor Age ◽

Human Myotubes ◽

Human Skeletal Muscle Cells

AbstractPrimary human myotubes represent an alternative system to intact skeletal muscle for the study of human diseases related to changes in muscle energy metabolism. This work aimed to study if fatty acid and glucose metabolism in human myotubes in vitro were related to muscle of origin, donor gender, age, or body mass index (BMI). Myotubes from a total of 82 donors were established from three different skeletal muscles, i.e., musculus vastus lateralis, musculus obliquus internus abdominis, and musculi interspinales, and cellular energy metabolism was evaluated. Multiple linear regression analyses showed that donor age had a significant effect on glucose and oleic acid oxidation after correcting for gender, BMI, and muscle of origin. Donor BMI was the only significant contributor to cellular oleic acid uptake, whereas cellular glucose uptake did not rely on any of the variables examined. Despite the effect of age on substrate oxidation, cellular mRNA expression of pyruvate dehydrogenase kinase 4 (PDK4) and peroxisome proliferator–activated receptor gamma coactivator 1 alpha (PPARGC1A) did not correlate with donor age. In conclusion, donor age significantly impacts substrate oxidation in cultured human myotubes, whereas donor BMI affects cellular oleic acid uptake.

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