骨骼肌线粒体动力学调节微循环低氧训练适应的机制

Normoxia and hypoxic exercise training can promote microcirculation function in muscle and other tissues, and oxygen consumption is essencial in microcirculation function. Researches indicate exercise training increases mitochondrial fusion and autophagy, and decreases mitochondrial fission, which appears a beneficial effect on oxygen consumption upon exercise. Whether normoxia and hypoxic exercise-induced enhancements of muscular microcirculation depend on alterations of mitochondrial dynamics (high level mitochondrial fusion and autophagy, repression of mitochondrial fission), which is unknown. Thus, this research will firstly investigate the changes of muscular microcirculation in response to normoxia exercise training, and discuss the characteristics of mitochondrial dynamics in different sensitive groups. Secondly, we will focus on the effects of different hypoxic training on muscular microcirculation, searching for the best intervention means. That work will illustrate the relation between microcirculation and mitochondrial dynamics. Thirdly, we also study the adaptation of microcirculation to a specific hypoxic training, and discuss the characteristics of mitochondrial dynamics in different sensitive groups. Then, we will put forward the functions of mitochondrial dynamics in microcirculation adaption to exercise training. This work mainly tests and verifies hypothesis that high levels of mitochondrial fusion and autophagy, and low level of mitochondrial fission will appear in specific groups, such as more sensitive group to exercise training and specific hypoxic training. This study reveals the mechanism of exercise training intervention on microcirculation, and establishes a theoretical foundation for athletic training work and exercise rehabilitation study fields.

常氧与低氧训练可促进肌肉等组织微循环功能，氧利用水平提高是微循环功能改善的前提。研究表明运动训练能提高骨骼肌线粒体融合及自噬，降低分裂，线粒体动力学（融合、分裂、自噬）对运动呈现有利于氧利用的应答。常氧及低氧训练对微循环的促进是否通过线粒体融合与自噬加速、分裂减速来实现，还不清楚。本研究先考察常氧运动后大鼠骨骼肌微循环变化，分析不同敏感性群体骨骼肌线粒体动力学特征；其次重点考察不同低氧训练干预骨骼肌微循环的效果，寻求最佳低氧训练干预模式，分析微循环低氧训练适应和线粒体动力学的关联；最后考察特定低氧训练下骨骼肌微循环的变化，观察不同敏感性群体骨骼肌线粒体动力学特征，分析其调节机制。本研究验证假说：常氧与不同模式低氧训练干预可改善骨骼肌微循环功能，敏感性高的群体具备更高线粒体融合、自噬水平，并且分裂降低，可揭示运动训练干预微循环的分子机制，为合理安排训练和运动康复领域微循环干预研究奠定基础。

微循环是血液和组织实现气体和物质交换的部位。低氧训练有效提高人体骨骼肌微循环机能，这种宏观适应与线粒体能量代谢有关。线粒体动力学包括线粒体融合与分裂，是实现线粒体合成与自噬的必要步骤，影响氧耗与分解代谢。低氧训练后，骨骼肌线粒体动力学的适应可能是微循环机能提高的潜在机制。. 第一，考察运动训练下，线粒体动力学与微循环的关联。发现中等负荷有氧运动能提高小鼠骨骼肌线粒体融合和合成能力，腓肠肌微循环机能（加热血流反应，基础血流）同步提高，骨骼肌CD31等血管标记物显著增加；AMPK激动剂激活线粒体合成与融合，上述指标也发生运动干预后的类似变化。提示运动训练后，骨骼肌线粒体动融合及合成能力与微循环机能同步提高。. 第二，考察低氧训练下，线粒体动力学与微循环的关联。发现低氧暴露、运动训练及低氧训练均能引起小鼠骨骼肌微循环机能提高，高住低练和低住高练模式不仅提高骨骼肌微循环机能，还有效提高线粒体分裂、合成及自噬信号。两种低氧训练干预后，骨骼肌线粒体适应信号与微循环机能变化信号均同步升高，关联趋势更明显。提示低氧训练提高骨骼肌微循环机能与线粒体动力学等适应信号有关联。. 第三，AMPK是控制线粒体动力学的激酶，制备肌肉AMPKα特异性敲除小鼠，发现骨骼肌线粒体自噬与合成信号降低，电镜观察发现线粒体动力学紊乱，线粒体体积变小，密度降低，且融合和分裂水平下降。敲除小鼠进行低氧训练后，线粒体动力学、合成及自噬信号均无显著变化，微循环机能也无适应性改变。健康鼠进行同样低氧训练干预，线粒体适应信号增强，微循环机能也明显提高。提示低氧训练中，骨骼肌线粒体动力学等适应信号的变化，发挥了积极作用，在骨骼肌微循环增强适应中扮演了关键作用。. 线粒体动力学等适应信号的积极变化，是低氧训练提高骨骼肌微循环机能关键机制，运动科学领域，通过营养或特定方法提高骨骼肌线粒体动力学等适应信号，是增强骨骼肌微循环的关键，也是是治疗肌肉微循环障碍疾病的潜在靶点。