低氧联合有氧运动激活Sima/dSir2信号通路介导NDA+/NADH平衡稳态的心脏增龄保护作用

Appropriate stimulus can activate the stress system to produce life-extending effects. NAD+ is necessary for the longevous function of dSir2. Sima is a core transcriptional regulation factor to trigger NAD+ synthesis by hypoxia. Our previous work suggest that Ldhal6b, the rate-limiting enzyme to catalyze NADH produce NAD+ under the condition of hypoxia, possess protection function of heart with age. In addition, as the key enzyme for NAD+ synthesis, Nmnat and CG9940 play an important role in delaying aging recession of cardiac function. We speculate that intermittent hypoxia can compensate limitation of the short lasting-duration of aerobic exercise, meanwhile, aerobic exercise can accelerate eliminating lactic acid, the byproduct from glycolysis. Hypoxia-exercise is ideal stressor for activation of Sima/NAD+/dSir2 signaling pathway. Supported by The National Natural Science Fund, we successfully solve the difficult problem of implementation of controlled exercise intervention on drosophila. This study intends to construct real-time energy metabolism expression system to establish hypoxia combined aerobic exercise Drosophila model using transgenic technology. Apply reverse genetics research strategy of signaling pathway, this research will study the effect of loss-of-function, gain-of-function and function rescue of Sima, dSir2, dFOXO, SOD2 gene on the function of aging heart, and discover the key genes, targets and downstream events of hypoxia and exercise induced activation of Sima/NAD+/dSir2 pathway. This research will be the first study to explore effects and mechanisms of life extension cardioprotection of hypoxia and exercise based on Drosophila model. This project can provide new genetic evidence for earlier scientific exploration for anti-aging methods related to the heart.

适宜刺激可激活机体应激系统产生延寿效应，NAD+为长寿基因dSir2发挥遗传延寿作用所必需，Sima是低氧触发NAD+合成的核心转录调节因子。前期研究发现，缺氧条件下催化NADH生成NAD+的限速酶Ldhal6b具有心脏增龄保护功能，NAD+合成关键酶Nmnat、CG9940在运动延缓心脏功能增龄衰退中发挥重要作用。我们推测，低氧可弥补有氧运动持续时间的局限，有氧运动可加速低氧副产物乳酸清除，两者结合是激活Sima/NAD+/dSir2通路理想应激源。我们前一个基金项目成功解决了对果蝇实施可控运动干预的难题，本项目拟采用转基因技术构建果蝇能量代谢实时表达体系建立低氧联合运动模型，通过研究Sima、dSir2、dFOXO、SOD2基因突变、功能拯救对中老龄果蝇心脏功能的影响，明确低氧联合运动调控Sima/NAD+/dSir2途径的关键基因和下游事件,为心脏抗衰老的科学探索提供新的遗传学证据。

利用心力衰竭模型筛选出最佳低氧年龄段与低氧持续时间，建立果蝇低氧运动模型，研究了低氧与运动改变心肌细胞Myosin和Actin对心脏泵血能力的影响，探讨了生命早期间歇性低氧联合规律运动促进dSir2表达对心脏功能的影响，以及规律运动介导心脏dSir2、Nmnat基因调控对高脂膳食或遗传诱发脂毒性心肌症的影和FOXO/SOD2介导规律攀爬运动改善高脂果蝇心脏功能。研究结果表明：规律运动能延缓增龄导致的果蝇心肌收缩蛋白及线粒体数量的减少，并维持心管舒张能力以提高射血分数，从而增强其心脏泵血能力。间歇性低氧训练和规律运动可增强心脏泵血功能，提升运动能力，间歇性低氧联合规律运动训练降低生命早期果蝇的心率，降低心脏纤维性震颤的发生，提升运动能力， dSIR2参与了这一过程。规律运动可激活NAD+/dSIR2通路改善心脏Nmnat和dSir2遗传表达改变诱发的脂毒性心肌症。运动通过FOXO/SOD2通路适当改善高脂引起的心功能障碍、纤维性颤动。研究为衰老及低氧联合运动延缓心脏功能机理研究提供了重要的基础研究证据。