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

Authors
Pan, Jeong HoonTang, JingsiKim, Young JunLee, Jin HyupShin, Eui-CheolZhao, JiangchaoKim, Kee-HongHwang, Kyung A.Huang, YanKim, Jae Kyeom
Issue Date
8월-2020
Publisher
MDPI
Keywords
IDH2 knockout; skeletal muscle; myogenesis; mitochondrial biogenesis; fatty acid oxidation; UCP1
Citation
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v.21, no.16
Indexed
SCIE
SCOPUS
Journal Title
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume
21
Number
16
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/54225
DOI
10.3390/ijms21165596
ISSN
1661-6596
Abstract
Mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDH2) catalyzes the oxidative decarboxylation of isocitrate into alpha-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, andFat1) 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.
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