Oxaloacetic acid induces muscle energy substrate depletion and fatigue by JNK-mediated mitochondrial uncoupling.
Cong YinRui QinZewei MaFan LiJiao LiuHong LiuGang ShuHairong XiongQingyan JiangPublished in: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (2024)
Fatigue is a common phenomenon closely related to physical discomfort and numerous diseases, which is severely threatening the life quality and health of people. However, the exact mechanisms underlying fatigue are not fully characterized. Herein, we demonstrate that oxaloacetic acid (OAA), a crucial tricarboxylic acid cycle intermediate, modulates the muscle fatigue. The results showed that serum OAA level was positively correlated with fatigue state of mice. OAA-treated induced muscle fatigue impaired the exercise performance of mice. Mechanistically, OAA increased the c-Jun N-terminal kinase (JNK) phosphorylation and uncoupling protein 2 (UCP2) levels in skeletal muscle, which led to decreased energy substrate 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. Our studies reveal a novel role of OAA in skeletal muscle metabolism, which would shed light on the mechanism of muscle fatigue and weakness.
Keyphrases
- skeletal muscle
- sleep quality
- insulin resistance
- signaling pathway
- cell death
- physical activity
- oxidative stress
- healthcare
- public health
- mental health
- high fat diet induced
- protein kinase
- nitric oxide
- risk assessment
- amino acid
- small molecule
- high intensity
- tyrosine kinase
- diabetic rats
- density functional theory
- quality improvement
- newly diagnosed
- social media
- endoplasmic reticulum stress
- wild type