Ludong University, City Yantai 264025, Shandong Province, China.
Key Laboratory of Physical Fitness and Exercise Rehabilitation of Hunan Province, Hunan Normal University, Chang Sha 410012, Hunan Province, China.
J Exp Biol. 2021 Sep 15;224(18). doi: 10.1242/jeb.242425.
Endurance exercise is an important way to resist and treat 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 pathway activation mediates endurance exercise-induced resistance to lipotoxic cardiomyopathy. The results showed that endurance exercise activated the cardiac Nmnat/NAD+/SIR2/FOXO pathway and the Nmnat/NAD+/SIR2/PGC-1α pathway, including up-regulating cardiac Nmnat, SIR2, FOXO and PGC-1α expression, superoxide dismutase (SOD) activity and NAD+ levels, and it prevented HFD-induced or cardiac Nmnat knockdown-induced cardiac lipid accumulation, malondialdehyde (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 knockdown flies. Therefore, the current results confirm that cardiac Nmnat/NAD+/SIR2 pathways are important antagonists of HFD-induced lipotoxic cardiomyopathy. Cardiac Nmnat/NAD+/SIR2 pathway activation is an important underlying molecular mechanism by which endurance exercise and cardiac Nmnat overexpression give protection against lipotoxic cardiomyopathy in Drosophila.
耐力运动是抵抗和治疗高脂肪饮食（HFD）诱导的脂毒性心肌病的重要方法，但潜在的分子机制尚不清楚。在这里，我们使用果蝇来确定心脏 Nmnat/NAD+/SIR2 途径的激活是否介导了耐力运动对脂毒性心肌病的抵抗作用。结果表明，耐力运动激活了心脏 Nmnat/NAD+/SIR2/FOXO 途径和 Nmnat/NAD+/SIR2/PGC-1α 途径，包括上调心脏 Nmnat、SIR2、FOXO 和 PGC-1α 的表达、超氧化物歧化酶（SOD）活性和 NAD+水平，并防止 HFD 诱导或心脏 Nmnat 敲低诱导的心脏脂质积累、丙二醛（MDA）含量和纤维颤动增加以及分数缩短减少。心脏 Nmnat 过表达也激活了心脏 Nmnat/NAD+/SIR2 途径并抵抗 HFD 诱导的心脏功能障碍，但不能防止 HFD 诱导的寿命缩短和运动障碍。运动改善了心脏 Nmnat 敲低果蝇的寿命和活动性。因此，目前的结果证实心脏 Nmnat/NAD+/SIR2 途径是 HFD 诱导的脂毒性心肌病的重要拮抗剂。心脏 Nmnat/NAD+/SIR2 途径的激活是耐力运动和心脏 Nmnat 过表达对果蝇脂毒性心肌病提供保护作用的重要潜在分子机制。
