TIGAR regulates mitochondrial functions through SIRT1-PGC1 pathway and translocation of TIGAR into mitochondria in skeletal muscle

TP53-induced glycolysis and apoptosis regulator (TIGAR), a glycolytic inhibitor, plays vital roles in regulating cellular metabolism and oxidative stress. However, the role of highly expressed TIGAR in skeletal muscle remains unexplored. In the present study, TIGAR levels varied in different skeletal muscles and fibers. An exhaustive swimming test with a load corresponding to 5% of body weight was utilized in mice to assess the effects of TIGAR on exercise-induced fatigue and muscle damage. The running time and metabolic indicators were significantly greater in wild-type (WT) mice compared with TIGAR knockout (KO) mice. Poor exercise capacity was accompanied by decreased type IIA fibers in TIGAR KO mice. Decreased mitochondrial number and mitochondrial oxidative phosphorylation were observed more in TIGAR KO mice than in WT mice, which were involved in sirtuin 1 (SIRT1)-mediated deacetylation of peroxisome proliferator-activated receptor coactivator 1 (PGC1), and resveratrol treatment in TIGAR KO mice can increase mitochondrial content and exercise time. Much more TIGAR was also detected in mitochondria during exhaustive exercise. In addition, TIGAR, rather than mitochondria-targeted TIGAR achieved by in vitro plasmid transfection, promoted SIRT1-PGC1 pathway. Glutathione S-transferase-TIGAR pull-down assay followed by liquid chromatography mass spectrometry found that TIGAR interacted with ATP synthase F1 subunit (ATP5A1), and its binding to ATP5A1 increased during exhaustive exercise. Overexpression of mitochondrial-TIGAR enhanced ATP generation, maintained mitochondrial membrane potential and reduced mitochondrial oxidative stress under hypoxia condition. Taken together, our results uncovered a novel role for TIGAR in mitochondrial regulation in fast-twitch oxidative skeletal muscle through SIRT1-PGC1 and translocation into mitochondria, which contribute to the increase in exercise endurance of mice.Geng, J., Wei, M., Yuan, X., Liu, Z., Wang, X., Zhang, D., Luo, L., Wu, J., Guo, W., Qin, Z.-H. TIGAR regulates mitochondrial functions through SIRT1-PGC1 pathway and translocation of TIGAR into mitochondria in skeletal muscle.