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Published on: January 12, 2016
Troponin T3 ameliorates sepsis-induced diaphragm dysfunction in rats through modulation of Cacna1s
Bing Wang1, Chang Liu1, Zhouli Ding1
1Department of Pulmonary Medicine, QingPu Branch of Zhongshan Hospital Affiliated to Fudan University, China.
Background:
Troponin T3 (TnT3) is involved in excitatory-contractile coupling in striated muscle and regulates Calcium voltage-gated channel subunit alpha1 S (Cacna1s) expression. Currently, the effect of TnT3/Cacna1s on the progression of sepsis-induced diaphragmatic dysfunction (SIDD) and the mechanism of action are unclear.
Methods:
A lipopolysaccharide (LPS)-induced C2C12 cell injury model was constructed in vitro, and a SIDD rat model was constructed by injecting LPS. The impacts of TnT3 on C2C12 cell viability and lactate dehydrogenase (LDH) release were determined by Cell Counting Kit-8 (CCK-8) assay and LDH kit. Inflammatory factors, SOD, GSH-px, MDA, ROS, and protein carbonyls were detected in C2C12 cells and SIDD rats by different kits, and the levels of muscle damage markers in rat serum were measured. Pathological staining was performed to assess pathological changes in rat diaphragm tissues as well as changes in apoptosis rates, and diaphragm mechanical indexes were examined. In addition, the expression of TnT3 and Cacna1s were assessed using qRT-PCR and Western blot, and myotubular atrophy-related proteins levels were assessed through Western blot.
Results:
In vitro, overexpression of TnT3 attenuated LPS-induced C2C12 cell injury and inhibited myotube atrophy, while reducing LDH release. In vivo, overexpression of TnT3 reduced LPS-induced changes in rat diaphragm mechanics, lowered levels of muscle damage markers, and attenuated diaphragm dysfunction, pathological damage, and apoptosis. Not only that, overexpression of TnT3 reduced MDA, ROS levels and protein carbonyl content, increased SOD and GSH-px activities, and reduced inflammatory factor levels in C2C12 cells and SIDD rat models. Overexpression of TnT3 upregulated Cacna1s, whereas silencing of Cacna1s attenuated the protective effect of TnT3 on SIDD cells and rat models.
Conclusion:
Overexpression TnT3 inhibits diaphragm dysfunction, increases cell viability and ameliorates diaphragm tissue damage through up-regulation of Cacna1s, which could serve as a therapeutic target for SIDD.
