Oxaloacetate Induces Muscle Energy Substrate Depletion and Fatigue by JNK-Mediated Mitochondrial Uncoupling

Abstract

Background: Tricarboxylic acid cycle intermediates (TCAi) in skeletal muscle, which secreted during muscle contraction, have diversity physiological roles in addition to energy supply. However, as a crucial TCAi, the effects of oxaloacetate (OAA) on skeletal muscle remain unknown. Methods: In vivo and ex vivo experiments were employed for muscle function and metabolism assessment. RNA-Sequencing, virus knockout, and drug inhibition were used for mechanism investigation. Findings: OAA induced muscle fatigue and impaired the exercise performance of mice. Mechanistically, OAA increased the c-Jun N-terminal kinase (JNK) phosphorylation and uncoupling protein 2 (UCP2) levels in the skeletal muscle, which led to decreased energy substrate storage and enhanced glycolysis. On the other hand, OAA boosted muscle mitochondrial oxidative phosphorylation uncoupled with energy production. In addition, either UCP2 knockout or JNK inhibition, totally reversed the effects of OAA on skeletal muscle. Therein, JNK mediated UCP2 activation with OAA-treated. Furthermore, OAA- induced muscle fatigue might not be through the directly exposed to muscle tissue, that was as a result of the unaltered muscle OAA content after acute OAA intragastric treatment or serum OAA level after chronic OAA treatment. Interpretation: This study identified a novel role of OAA in the skeletal muscle metabolism and fatigue, which may shed light on the mechanism of clinical muscle dysfunctions due to abnormal metabolism, such as muscle fatigue and weakness. Funding Statement: This work was supported by the Major Program of the National Natural Science Foundation of China (Grant No. 31790411 to Q.J.); Local Innovative and Research Teams Project of Guangdong Province (Grant No. 2019BT02N630 to G.S.); and National Key Point Research and Invention Program (Grant No. 2018YFD0500403 to G.S.). Declaration of Interests: The authors declare no conflict of interests. Ethics Approval Statement: The study was approved by the College of Animal Science, South China Agricultural University. All experiments were conducted in accordance with The Instructive Notions with Respect to Caring for Laboratory Animals (Ministry of Science and Technology, Beijing, China).