IDH2 Deficiency Disrupts Energy Homeostasis and Skeletal Muscle Development by Upregulating UCP1 Expression in Mice
Authors: Tang Jingsi , Pan Jeong Hoon , Zhao Jiangchao , Kim Jae Kyeom , Huang Yan 
Published: June 2021

Isocitrate dehydrogenase 2 (IDH2) is a mitochondrial specific enzyme that catalyses the oxidative decarboxylation of isocitrate into α‐ketoglutarate with concurrent reduction of NADP+ to NADPH. We previous reported that IDH2 knock‐out (KO) increased obesity resistance via UCP1‐mediated enhanced energy expenditure in adipose and liver tissues. Since skeletal muscle is the most mitochondria abundant tissue and is a major site for energy expenditure, we here examined the effects of IDH2 KO on skeletal muscle energy homeostasis and its growth. Calf skeletal muscle samples (i.e., mixed part of soleus, gastrocnemius, and plantaris muscles) were harvested from 11‐week‐old male IDH2 KO (n=4) and wild type (WT; C57BL/6; n=4) mice, and a ratio of skeletal muscle weight to body weight was measured. Subsequently, marker of mitochondrial DNA to nucleic DNA ratio was measured by PCR analysis. In addition, mRNA expression levels involved in fatty acid β‐oxidation (CPT1 and FAT), adipogenesis (PPARγ, C/EBPα, C/EBPβ, aP2, and ZFP423), thermogenesis (UCP1, BMP7, and PRDM16), myogenesis (MRF4 and MyoD), and mitochondria biogenesis (PGC‐1α, TFAM, ERRα, and MFN2) were compared. Interestingly, a ratio of skeletal muscle weight to body weight was significantly lower in IDH2 KO mice compared to that of WT mice (P=0.0004). Further, mitochondrial content was relatively lower in skeletal muscle of IDH2 KO mice than the WT mice albeit it was not statistically significant (P=0.09). In consistent with the muscle mass, there were trends of decrease in the expressions of myogenesis (MyoD, P=0.07) as well as mitochondrial biogenesis genes in IDH2 KO mice (PGC‐1α, P<0.05; TFAM, P=0.07). Last, the expression level of UCP1, a hallmark of thermogenesis, was remarkably increased in skeletal muscle whereas adipogenesis pathway (PPARγ, P<0.005; C/EBPβ, P=0.06; ZFP423, P<0.05) was down‐regulated in skeletal muscle of IDH2 KO mice. However, UCP1 seems not directly regulated by the expression of BMP7 or PRDM16 as the expression of BMP7 and PRDM16 was also down‐regulated in IDH2 KO mice. Taken together, our study suggests that IDH2 deficiency may upregulate UCP1‐mediated thermogenesis possibly to adopt limited NADPH supply. In turn, the thermogenesis‐induced energy imbalance may cause suppression of myogenesis, mitochondria biogenesis, adipogenic signaling pathway, and skeletal muscle growth. Our study will provide scientific background to further studies on the mechanistic functions of IDH2 in skeletal muscle development.Support or Funding InformationThis work was supported by the University of Arkansas, VPRED Start‐up fund (KJK, and PJH). Support has been provided in part by the Arkansas Biosciences Institute, a partnership of scientists from Arkansas Children's Hospital, Arkansas State University, the University of Arkansas‐Division of Agriculture, the University of Arkansas, Fayetteville, and the University of Arkansas for Medical Sciences. The Arkansas Biosciences Institute is the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000 (JKK, JHP, KEB, and BCK).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.