The activation of cardiac Nmnat/NAD+/SIR2 pathways mediates endurance exercise resistance to lipotoxic cardiomyopathy in aging Drosophila.
The activation of cardiac Nmnat/NAD+/SIR2 pathways mediates endurance exercise resistance to lipotoxic cardiomyopathy in aging Drosophila.
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DOI：
10.1242/jeb.242425
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发表时间：
2021-09
期刊：
影响因子：
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通讯作者：
Deng-tai Wen;Lan Zheng;Kai Lu;Wen-qi Hou
中科院分区：
文献类型：
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作者：
Deng-tai Wen;Lan Zheng;Kai Lu;Wen-qi Hou
耐力运动是抵抗和治疗高脂饮食（HFD）诱导的脂毒性心肌病的重要途径，但其潜在的分子机制尚不清楚。在这里，我们使用果蝇来鉴定心脏Nmnat/NAD+/SIR2通路的激活是否可以介导耐力运动对脂毒性心肌病的抵抗。结果表明，耐力运动激活了心肌Nmnat/NAD+/SIR2/FOXO通路和Nmnat/NAD+/SIR2/PGC-1α通路，上调了心肌Nmnat、SIR2、FOXO、PGC-1α表达、SOD活性和NAD+水平，阻止了hfd诱导或Nmnat敲低诱导的心肌脂质积累，MDA含量和纤颤增加，分数缩短减少。心脏Nmnat的过表达也激活了心脏Nmnat/NAD+/SIR2通路，并抵抗了hfd诱导的心功能障碍，但对hfd诱导的寿命缩短和运动障碍没有保护作用。运动改善了心脏Nmnat敲除果蝇的寿命和活动能力。因此，目前的研究结果证实，心脏Nmnat/NAD+/SIR2通路是hfd诱导的脂毒性心肌病的重要拮抗剂。心肌Nmnat/NAD+/SIR2通路激活是果蝇耐力运动和心肌Nmnat过表达抗脂毒性心肌病的重要潜在分子机制。
Endurance exercise is an important way to resist and treat a high-fat-diet(HFD)-induced lipotoxic cardiomyopathy, but the underlying molecular mechanisms are poorly understood. Here, we used Drosophila to identify whether cardiac Nmnat/NAD+/SIR2 pathways activation could mediate endurance exercise resistance to lipotoxic cardiomyopathy. The results showed that endurance exercise activated the cardiac Nmnat/NAD+/SIR2/FOXO pathway and Nmnat/NAD+/SIR2/PGC-1α pathway, including up-regulating cardiac Nmnat, SIR2, FOXO, PGC-1α expression, SOD activity, and NAD+ level, and it prevented HFD-induced or cardiac Nmnat knock-down-induced cardiac lipid accumulation, MDA content and fibrillation increase, and fractional shortening decrease. Cardiac Nmnat overexpression also activated heart Nmnat/NAD+/SIR2 pathways and resisted HFD-induced cardiac malfunction, but it could not protect against HFD-induced lifespan reduction and locomotor impairment. Exercise improved lifespan and mobility in cardiac Nmnat knock-down flies. Therefore, current results confirmed that cardiac Nmnat/NAD+/SIR2 pathways were important antagonists of HFD-induced lipotoxic cardiomyopathy. The cardiac Nmnat/NAD+/SIR2 pathways activation was the important underlying molecular mechanism of endurance exercise and cardiac Nmnat overexpression against lipotoxic cardiomyopathy in Drosophila.