Octopamine controls adaptation to endurance exercise in Drosophila

章鱼胺控制果蝇对耐力运动的适应 摘要 运动被广泛认为是对抗代谢功能障碍和年龄相关性疾病的有力干预措施。 疾病然而，许多患者由于疾病，受伤或生活方式而无法长时间锻炼 因素此外，个体的遗传差异使一些个体无法充分受益， 锻炼的在这里，我们建议使用果蝇作为遗传模型，以确定特定的遗传 解释运动反应个体差异的途径。我们已经开发出了第一个耐力 果蝇的运动平台。使用这种模式，我们发现， 分泌去甲肾上腺素能胺章鱼胺是必要的，足以提供的好处， 运动到久坐的苍蝇。我们还确定了不同的章鱼胺水平是女性 与雄性相比，果蝇的运动反应不足。在这里，我们建议确定下游 章鱼胺提供这些益处的机制。为了做到这一点，我们将利用遗传 果蝇模型中可用的工具，以实现以下目标。首先，我们将识别组织特异性 在运动过程中使用组织特异性的，可诱导的敲低对章鱼胺受体的需求。第二、 我们将使用单一的， cell RNAseq来鉴定运动激活的性别特异性转录物。第三，我们将确定机制 慢性运动中章鱼胺能神经元可塑性来源和需要 荧光双标记和共聚焦显微镜。因为已知哺乳动物会上调 运动中的章鱼胺样分子去甲肾上腺素，我们希望我们发现的机制是 包括人类在内的哺乳动物中保存的。这些发现将为提供代谢益处开辟道路， 通过药理学或神经刺激对久坐患者进行锻炼。

Octopamine controls adaptation to endurance exercise in Drosophila Abstract Exercise is widely recognized as a powerful intervention against metabolic dysfunction and age-related disease. However, many patients are unable to exercise for extended periods due to illness, injury or lifestyle factors. Furthermore, individual genetic differences prevent some individuals from receiving the full benefits of exercise. Here, we propose to use the fruit fly Drosophila as a genetic model to identify specific genetic pathways that account for individual differences in exercise response. We have developed the first endurance exercise platform for Drosophila. Using this paradigm, we have discovered that activation of the neurons that secrete the noradrenergic amine octopamine is both necessary and sufficient to provide the benefits of exercise to sedentary flies. We have also identified differential octopamine levels as the reason why female flies have a deficient exercise response in comparison to males. Here, we propose to identify the downstream mechanism by which octopamine provides these benefits. To do this, we will take advantage of the genetic tools available in the fruit fly model to pursue the following aims. First, we will identify tissue-specific requirements for octopamine receptors during exercise using tissue-specific, inducible knockdowns. Second, we will identify the mechanistic targets for increased excitability in male octopaminergic neurons using single- cell RNAseq to identify sex-specific transcripts activated by exercise. Third, we will identify the mechanistic source and requirement for neural plasticity of octopaminergic neurons during chronic exercise using fluorescent double labelling and confocal microscopy. Because mammals are known to upregulate secretion of the octopamine-like molecule norepinephrine during exercise, we expect the mechanisms we find to be conserved in mammals, including humans. These findings will open the way to provide metabolic benefits of exercise to sedentary patients through pharmacology or neural stimulation.