scholarly journals IDH2 Deficiency Is Critical in Myogenesis and Fatty Acid Metabolism in Mice Skeletal Muscle

2020 ◽  
Vol 21 (16) ◽  
pp. 5596
Author(s):  
Jeong Hoon Pan ◽  
Jingsi Tang ◽  
Young Jun Kim ◽  
Jin Hyup Lee ◽  
Eui-Cheol Shin ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Energy Homeostasis ◽  
Muscle Development ◽  
Acid Metabolism ◽  
Uncoupling Protein ◽  
Acid Oxidation ◽  
Oxidative Decarboxylation ◽  
Muscle Weight

Mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2) catalyzes the oxidative decarboxylation of isocitrate into α-ketoglutarate with concurrent reduction of NADP+ to NADPH. However, it is not fully understood how IDH2 is intertwined with muscle development and fatty acid metabolism. Here, we examined the effects of IDH2 knockout (KO) on skeletal muscle energy homeostasis. Calf skeletal muscle samples from 10-week-old male IDH2 KO and wild-type (WT; C57BL/6N) mice were harvested, and the ratio of skeletal muscle weight to body and the ratio of mitochondrial to nucleic DNA were measured. In addition, genes involved in myogenesis, mitochondria biogenesis, adipogenesis, and thermogenesis were compared. Results showed that the ratio of skeletal muscle weight to body weight was lower in IDH2 KO mice than those in WT mice. Of note, a noticeable shift in fiber size distribution was found in IDH2 KO mice. Additionally, there was a trend of a decrease in mitochondrial content in IDH2 KO mice than in WT mice (p = 0.09). Further, mRNA expressions for myogenesis and mitochondrial biogenesis were either decreased or showed a trend of decrease in IDH2 KO mice. Moreover, genes for adipogenesis pathway (Pparg, Znf423, and Fat1) were downregulated in IDH2 KO mice. Interestingly, mRNA and protein expression of uncoupling protein 1 (UCP1), a hallmark of thermogenesis, were remarkably increased in IDH2 KO mice. In line with the UCP1 expression, IDH2 KO mice showed higher rectal temperature than WT mice under cold stress. Taken together, IDH2 deficiency may affect myogenesis, possibly due to impairments of muscle generation and abnormal fatty acid oxidation as well as thermogenesis in muscle via upregulation of UCP1.

scholarly journals The Role of Atypical Cannabinoid Ligands O-1602 and O-1918 on Skeletal Muscle Homeostasis with a Focus on Obesity

2020 ◽  
Vol 21 (16) ◽  
pp. 5922
Author(s):  
Anna C. Simcocks ◽  
Lannie O’Keefe ◽  
Kayte A. Jenkin ◽  
Lauren M. Cornall ◽  
Esther Grinfeld ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Mrna Expression ◽  
Fatty Acid Metabolism ◽  
Energy Homeostasis ◽  
Acid Metabolism ◽  
Oxidative Capacity ◽  
C2c12 Myotubes ◽  
Sprague Dawley ◽  
White Gastrocnemius

O-1602 and O-1918 are atypical cannabinoid ligands for GPR55 and GPR18, which may be novel pharmaceuticals for the treatment of obesity by targeting energy homeostasis regulation in skeletal muscle. This study aimed to determine the effect of O-1602 or O-1918 on markers of oxidative capacity and fatty acid metabolism in the skeletal muscle. Diet-induced obese (DIO) male Sprague Dawley rats were administered a daily intraperitoneal injection of O-1602, O-1918 or vehicle for 6 weeks. C2C12 myotubes were treated with O-1602 or O-1918 and human primary myotubes were treated with O-1918. GPR18 mRNA was expressed in the skeletal muscle of DIO rats and was up-regulated in red gastrocnemius when compared with white gastrocnemius. O-1602 had no effect on mRNA expression on selected markers for oxidative capacity, fatty acid metabolism or adiponectin signalling in gastrocnemius from DIO rats or in C2C12 myotubes, while APPL2 mRNA was up-regulated in white gastrocnemius in DIO rats treated with O-1918. In C2C12 myotubes treated with O-1918, PGC1α, NFATc1 and PDK4 mRNA were up-regulated. There were no effects of O-1918 on mRNA expression in human primary myotubes derived from obese and obese T2DM individuals. In conclusion, O-1602 does not alter mRNA expression of key pathways important for skeletal muscle energy homeostasis in obesity. In contrast, O-1918 appears to alter markers of oxidative capacity and fatty acid metabolism in C2C12 myotubes only. GPR18 is expressed in DIO rat skeletal muscle and future work could focus on selectively modulating GPR18 in a tissue-specific manner, which may be beneficial for obesity-targeted therapies.

Effects of fasting on muscle mitochondrial energetics and fatty acid metabolism in Ucp3(−/−) and wild-type mice

2001 ◽  
Vol 281 (5) ◽  
pp. E975-E982 ◽  
Author(s):  
Véronic Bézaire ◽  
Wolfgang Hofmann ◽  
John K. G. Kramer ◽  
Leslie P. Kozak ◽  
Mary-Ellen Harper
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Uncoupling Protein ◽  
Resting Metabolic Rate ◽  
Proton Leak ◽  
Acid Oxidation ◽  
Protonmotive Force ◽  
Wild Type ◽  
Skeletal Muscle Mitochondria

Uncoupling protein-3 (UCP3) is a mitochondrial carrier protein of as yet undefined physiological function. To elucidate characteristics of its function, we studied the effects of fasting on resting metabolic rate, respiratory quotient, muscle Ucp3expression, and mitochondrial proton leak in wild-type and Ucp3(−/−) mice. Also analyzed were the fatty acid compositions of skeletal muscle mitochondria in fed and fasted Ucp3(−/−) and wild-type mice. In wild-type mice, fasting caused significant increases in Ucp3 (4-fold) and Ucp2 (2-fold) mRNA but did not significantly affect mitochondrial proton leak. State 4 oxygen consumption was not affected by fasting in either of the two groups. However, protonmotive force was consistently higher in mitochondria of Ucp3(−/−) animals ( P = 0.03), and fasting further augmented protonmotive force in Ucp3(−/−) mice; there was no effect in wild-type mitochondria. Resting metabolic rates decreased with fasting in both groups. Ucp3(−/−) mice had higher respiratory quotients than wild-type mice in fed resting states, indicating impaired fatty acid oxidation. Altogether, results show that the fasting-induced increases in Ucp2 and Ucp3 do not correlate with increased mitochondrial proton leak but support a role for UCP3 in fatty acid metabolism.

Uncoupling protein 3 and fatty acid metabolism

2001 ◽  
Vol 29 (6) ◽  
pp. 785-791 ◽  
Author(s):  
A. G. Dulloo ◽  
S. Samec ◽  
J. Seydoux
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Fatty Acid ◽  
Lipid Oxidation ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Gene Knockout ◽  
Uncoupling Protein ◽  
Brown Adipose ◽  
Genes Encoding

A role for uncoupling protein (UCP) 3 in fatty acid metabolism is reviewed within the context of our proposal, first put forward in 1998, that this homologue of UCP1 may be involved in the regulation of lipids as fuel substrate rather than in the mediation of thermogenesis. Since then, the demonstrations of muscle-type differences in UCP3 gene regulation in response to dietary manipulations (starvation, high-fat feeding) or to pharmacological interferences with the flux of lipid substrates between adipose-tissue stores and skeletal-muscle mitochondrial oxidation are all in accord with this proposed role for UCP3 in regulating lipids as fuel substrate. However, given the current limitations of gene-knockout technology for evaluating/interpreting the functional importance of genes encoding mitochondrial membrane proteins, the transition from ‘associative’ to ‘cause-and-effect’ evidence for a physiological role of UCP3 in regulating fatty acid metabolism will have to await the development of assays that are sensitive to changes in UCP3 activity. Furthermore, in evaluating the physiological regulators of UCP3, the available evidence points to the existence of adipose-derived factor(s) which, independently of circulating levels of free fatty acids, initiates events leading to the transcription of genes encoding UCP3 and key enzymes of lipid oxidation in the fast glycolytic or fast oxidative-glycolytic muscles, i.e. in the bulk of the skeletal-muscle mass. It is proposed that in tissues where UCP3 co-exists with UCP2 (skeletal muscle, brown adipose tissue, heart) they may act in concert in the overall regulation of lipid oxidation, concomitant to the prevention of lipid-induced oxidative damage.

scholarly journals Genome-Wide Expression Profiling of mRNAs, lncRNAs and circRNAs in Skeletal Muscle of Two Different Pig Breeds

Animals ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 3169
Author(s):  
Xinhua Hou ◽  
Ligang Wang ◽  
Fuping Zhao ◽  
Xin Liu ◽  
Hongmei Gao ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Muscle Development ◽  
Target Genes ◽  
Acid Metabolism ◽  
Differentially Expressed ◽  
Rna Seq ◽  
Skeletal Muscle Development ◽  
Pig Breeds

RNA-Seq technology is widely used to analyze global changes in the transcriptome and investigate the influence on relevant phenotypic traits. Beijing Black pigs show differences in growth rate and meat quality compared to western pig breeds. However, the molecular mechanisms responsible for such phenotypic differences remain unknown. In this study, longissimus dorsi muscles from Beijing Black and Yorkshire pigs were used to construct RNA libraries and perform RNA-seq. Significantly different expressions were observed in 1051 mRNAs, 322 lncRNAs, and 82 circRNAs. GO and KEGG pathway annotation showed that differentially expressed mRNAs participated in skeletal muscle development and fatty acid metabolism, which determined the muscle-related traits. To explore the regulatory role of lncRNAs, the cis and trans-target genes were predicted and these lncRNAswere involved in the biological processes related to skeletal muscle development and fatty acid metabolismvia their target genes. CircRNAs play a ceRNA role by binding to miRNAs. Therefore, the potential miRNAs of differentially expressed circRNAs were predicted and interaction networks among circRNAs, miRNAs, and key regulatory mRNAs were constructed to illustrate the function of circRNAs underlying skeletal muscle development and fatty acid metabolism. This study provides new clues for elucidating muscle phenotypic variation in pigs.

Role of the AMP-activated protein kinase in regulating fatty acid metabolism during exerciseThis paper is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal’s usual peer review process.

2009 ◽  
Vol 34 (3) ◽  
pp. 315-322 ◽  
Author(s):  
Gregory R. Steinberg
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Adipose Tissue ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Moderate Intensity ◽  
Amp Activated Protein Kinase

During moderate-intensity exercise, fatty acids are the predominant substrate for working skeletal muscle. The release of fatty acids from adipose tissue stores, combined with the ability of skeletal muscle to actively fine tune the gradient between fatty acid and carbohydrate metabolism, depending on substrate availability and energetic demands, requires a coordinated system of metabolic control. Over the past decade, since the discovery that AMP-activated protein kinase (AMPK) was increased in accordance with exercise intensity, there has been significant interest in the proposed role of this ancient stress-sensing kinase as a critical integrative switch controlling metabolic responses during exercise. In this review, studies examining the role of AMPK as a regulator of fatty acid metabolism in both adipose tissue and skeletal muscle during exercise will be discussed. Exercise induces activation of AMPK in adipocytes and regulates triglyceride hydrolysis and esterfication through phosphorylation of hormone sensitive lipase (HSL) and glycerol-3-phosphate acyl-transferase, respectively. In skeletal muscle, exercise-induced activation of AMPK is associated with increases in fatty acid uptake, phosphorylation of HSL, and increased fatty acid oxidation, which is thought to occur via the acetyl-CoA carboxylase-malony-CoA-CPT-1 signalling axis. Despite the importance of AMPK in regulating fatty acid metabolism under resting conditions, recent evidence from transgenic models of AMPK deficiency suggest that alternative signalling pathways may also be important for the control of fatty acid metabolism during exercise.

scholarly journals Fatty acid oxidation inhibitor etomoxir suppresses tumor progression and induces cell cycle arrest via PPARγ-mediated pathway in bladder cancer

2019 ◽  
Vol 133 (15) ◽  
pp. 1745-1758 ◽  
Author(s):  
Songtao Cheng ◽  
Gang Wang ◽  
Yejinpeng Wang ◽  
Liwei Cai ◽  
Kaiyu Qian ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bladder Cancer ◽  
Fatty Acid ◽  
Tumor Progression ◽  
Cell Cycle Arrest ◽  
Fatty Acid Oxidation ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Acid Oxidation ◽  
Cycle Arrest

Abstract Tumor cells rely on aerobic glycolysis as their main energy resource (Warburg effect). Recent research has highlighted the importance of lipid metabolism in tumor progression, and certain cancers even turn to fatty acids as the main fuel. Related studies have identified alterations of fatty acid metabolism in human bladder cancer (BCa). Our microarray analysis showed that fatty acid metabolism was activated in BCa compared with normal bladder. The free fatty acid (FFA) level was also increased in BCa compared with paracancerous tissues. Inhibition of fatty acid oxidation (FAO) with etomoxir caused lipid accumulation, decreased adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide phosphate (NADPH) levels, suppressed BCa cell growth in vitro and in vivo, and reduced motility of BCa cells via affecting epithelial–mesenchymal transition (EMT)-related proteins. Furthermore, etomoxir induced BCa cell cycle arrest at G0/G1 phase through peroxisome proliferator-activated receptor (PPAR) γ-mediated pathway with alterations in fatty acid metabolism associated gene expression. The cell cycle arrest could be reversed by PPARγ antagonist GW9662. Taken together, our results suggest that inhibition of FAO with etomoxir may provide a novel avenue to investigate new therapeutic approaches to human BCa.

scholarly journals PCB11 Metabolite, 3,3’-Dichlorobiphenyl-4-ol, Exposure Alters the Expression of Genes Governing Fatty Acid Metabolism in the Absence of Functional Sirtuin 3: Examining the Contribution of MnSOD

Antioxidants ◽  
2018 ◽  
Vol 7 (9) ◽  
pp. 121 ◽  
Author(s):  
Sinthia Alam ◽  
Gwendolyn Carter ◽  
Kimberly Krager ◽  
Xueshu Li ◽  
Hans-Joachim Lehmler ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Mitochondrial Respiration ◽  
Mammalian Cells ◽  
Acid Metabolism ◽  
Cellular Growth ◽  
Acid Oxidation ◽  
Sirtuin 3 ◽  
Endogenous Fatty Acid ◽  
Mnsod Activity

Although the production of polychlorinated biphenyls (PCBs) is prohibited, the inadvertent production of certain lower-chlorinated PCB congeners still threatens human health. We and others have identified 3,3’-dichlorobiphenyl (PCB11) and its metabolite, 3,3’-dichlorobiphenyl-4-ol (4OH-PCB11), in human blood, and there is a correlation between exposure to this metabolite and mitochondrial oxidative stress in mammalian cells. Here, we evaluated the downstream effects of 4OH-PCB11 on mitochondrial metabolism and function in the presence and absence of functional Sirtuin 3 (SIRT3), a mitochondrial fidelity protein that protects redox homeostasis. A 24 h exposure to 3 μM 4OH-PCB11 significantly decreased the cellular growth and mitochondrial membrane potential of SIRT3-knockout mouse embryonic fibroblasts (MEFs). Only wild-type cells demonstrated an increase in Manganese superoxide dismutase (MnSOD) activity in response to 4OH-PCB11–induced oxidative injury. This suggests the presence of a SIRT3-mediated post-translational modification to MnSOD, which was impaired in SIRT3-knockout MEFs, which counters the PCB insult. We found that 4OH-PCB11 increased mitochondrial respiration and endogenous fatty-acid oxidation-associated oxygen consumption in SIRT3-knockout MEFs; this appeared to occur because the cells exhausted their reserve respiratory capacity. To determine whether these changes in mitochondrial respiration were accompanied by similar changes in the regulation of fatty acid metabolism, we performed quantitative real-time polymerase chain reaction (qRT-PCR) after a 24 h treatment with 4OH-PCB11. In SIRT3-knockout MEFs, 4OH-PCB11 significantly increased the expression of ten genes controlling fatty acid biosynthesis, metabolism, and transport. When we overexpressed MnSOD in these cells, the expression of six of these genes returned to the baseline level, suggesting that the protective role of SIRT3 against 4OH-PCB11 is partially governed by MnSOD activity.

Fatty Acid Oxidation by Skeletal Muscle During Rest and Activity

1958 ◽  
Vol 194 (2) ◽  
pp. 379-386 ◽  
Author(s):  
Irving B. Fritz ◽  
Don G. Davis ◽  
Robert H. Holtrop ◽  
Harold Dundee
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Palmitic Acid ◽  
Fatty Acid Oxidation ◽  
Latissimus Dorsi ◽  
Acid Metabolism ◽  
Fat Metabolism ◽  
Acid Oxidation ◽  
Stimulation Of

The metabolism of C14-labeled acetate, octanoate and palmitate by isolated skeletal muscle (latissimus dorsi and diaphragm) from normal, fed rats has been examined. The rates at which these substrates were converted to C14O2 have been shown to vary with concentration, temperature, functional state of the muscle, and the presence of albumin. Increased concentration of fatty acids led to enhanced conversion of substrate to C14O2. Electrical stimulation of muscles under tension resulted in approximately a 60% increase in oxygen consumption and about a 100% rise in fatty acid oxidation. The addition of glucose did not alter the rate of fatty acid metabolism by muscle. The addition of bovine albumin at concentrations up to approximately 1 µm albumin/7 µm palmitate resulted in augmented palmitic acid oxidation. However, at concentrations of albumin greater than 1 µm albumin/7 µm palmitate, palmitic acid degradation by resting diaphragm was inhibited, suggesting a firmer binding of fatty acid to albumin. The Q10 for palmitic acid oxidation by resting diaphragm was 2.23 in the absence of added albumin between 25° and 37°C. The data are discussed in relation to the present concepts of fat metabolism and transport in vivo. It is suggested that fat degradation in isolated muscle may provide an energy source during activity.

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