Role of NOD-like receptor family, pyrin domain containing 3 inflammasome in the hypoxia-induced skeletal muscle mitochondrial dysfunction / 中国组织工程研究

ABSTRACT

BACKGROUND:Whether NOD-like receptor family,pyrin domain containing 3 (NLRP3) inflammasome is involved in hypoxia-induced skeletal muscle mitochondrial dysfunction,and the underlying mechanism remain unclear.OBJECTIVE:To observe the effect of NLRP3 inflammasome inhibitor VX-765 on skeletal muscle mitochondrial function,and to explore the role of NLRP3 inflammasome in hypoxia-induced mitochondrial dysfunction.METHODS:Thirty Sprague-Dawley rats were randomly divided into three groupsnormoxia,hypoxia,and hypoxia plus VX-765 groups.The rats in the hypoxia group were subjected to hypoxia exposure in normobaric hypoxic tent with 11.3％ O2.The hypoxia plus VX-765 group rats were given the intraperitoneal injection of VX-765 (50 mg/kg) daily.All of the interventions lasted for 4 weeks.RESULTS AND CONCLUSION:VX-765 in hypoxia markedly inhibited the expression of NLRP3 and apoptosis-associated speck-like protein,attenuated caspase-1 activity and interleukin-1β content,and suppressed mitochondrial H2O2 generation.In addition,VX-765 in hypoxia markedly enhanced the expression of mitochondrial peroxisome proliferator-activated receptor y coactivator 1-α and cyclooxygenase ⅣV,elevated mitochondrial membrane potent and ATP synthetase activity.These results indicate that hypoxia induces skeletal muscle dysfunction through activating NLRP3 inflammasome and impairing mitochondrial function.The hypoxia-induced mitochondrial dysfunction enhances reactive oxygen species generation and further triggers interleukin-1 β production via the NLRP3 inflammasome activation.In turn,interleukin-lβ further impairs mitochondrial function through suppresseing peroxisome proliferator-activated receptor y coactivator 1 o,resulting in a vicious circle between NLRP3 inflammasome activation and mitochondrial dysfunction.