Is the exercise-regulated myokine-like small molecule beta-aminoisobutyric acid a paracrine signal and exercise mimetic?

锻炼是在个人的一生中保持健康生活方式的重要组成部分。然而，身体如何将运动的努力转化为健康的改善，还没有完全了解。运动需要身体不同器官和组织之间的复杂沟通：蛋白质PGC-1 α协调身体对运动的一些反应，特别是肌肉。然而，PGC-1 α如何与肌肉细胞外的其他组织“交谈”尚不清楚。我们之前的研究表明，在运动过程中，PGC-1 α导致肌肉细胞释放一种名为β-氨基异丁酸（BAIBA）的信使分子。我们发现，BAIBA通过使储存能量的白色脂肪细胞变得更像燃烧卡路里的棕色脂肪细胞来改变脂肪细胞。肌肉在运动中产生的BAIBA被释放到血液中，促进其他组织的新陈代谢。与未经治疗的小鼠相比，给予BAIBA的小鼠燃烧更多的卡路里，体重增加更少，葡萄糖代谢更好。我们还发现，血液中含有更多BAIBA的人的健康风险指标较低，如高胆固醇水平和高血糖。在我们最近的研究中，我们和其他研究人员发现，BAIBA也可能将信息传递回肌肉。在这项拟议的调查中，我们问是否BAIBA因此可能有助于肌肉适应运动的方式，以提高运动能力和表现。我们还旨在确定BAIBA是否可以模拟运动对肌肉的某些影响。具体而言，本研究将研究BAIBA如何影响调节运动适应的基因和蛋白质，以及与运动适应相关的方面，包括燃料代谢，蛋白质代谢，肌肉结构和刺激人体肌肉细胞中的血管生长。我们将研究是否给予小鼠BAIBA改善其肌肉执行工作，使用燃料（脂肪和碳水化合物）和抵抗疲劳的能力。我们还将研究BAIBA是否会导致小鼠肌肉激活与运动相关的基因，以增加线粒体（细胞的“发电站”）的数量，将燃料转化为能量，改变肌肉的结构以类似于运动训练的效果，并增加肌肉血液供应。最后，我们将研究白巴对肌肉的运动模拟作用是否会导致运动表现、效率和肌肉代谢的改善。最终，本研究有能力确定BAIBA是否可以模拟肌肉运动的效果，以提高肌肉性能。这在运动/身体表现受损或需要改善的情况下可能很重要，例如在受衰弱性肌肉萎缩疾病影响的个体中，或在运动营养中。使用BAIBA刺激肌肉运动方面的能力对于因残疾或疾病而无法进行运动训练的人也很重要。

Exercise is an important part of maintaining a healthy lifestyle across an individual's lifespan. Just how the body turns the efforts of exercise into improvements in health, however, is not fully understood. Exercise requires complex communication between different organs and tissues in the body: the protein PGC-1alpha coordinates some of the body's response to exercise, particularly in muscle. How PGC-1alpha "talks" to other tissues outside of muscle cells, though, was unknown. Our previous research demonstrated that during exercise, PGC-1alpha causes muscle cells to release a messenger molecule called Beta-aminoisobutyric acid (BAIBA). We found that BAIBA modifies fat cells by making energy-storing white fat cells become more like calorie-burning brown fat cells. The BAIBA produced in muscle in response to exercise is released into the blood and boosts metabolism in other tissues. Mice given BAIBA burned more calories, gained less weight and had better glucose metabolism than untreated mice. We also found that people with more BAIBA in their blood had lower indicators of health risk such as high cholesterol levels and high blood glucose. In our recent research, we, and other researchers, have seen that BAIBA may also communicate messages back to muscle. In this proposed investigation, we ask whether BAIBA may therefore contribute to the way muscles adapt to exercise to produce improvements in exercise capability and performance. We also aim to determine if BAIBA can mimic some of the effects of exercise in muscle.Specifically, this study will investigate how BAIBA affects genes and proteins regulating, and associated with, aspects of exercise adaptation, including fuel metabolism, protein metabolism, muscle structure and stimulation of blood vessel growth in human muscle cells. We will examine whether giving BAIBA to mice improves the ability of their muscles to perform work, use fuel (fat and carbohydrates) and to resist tiring. We will also investigate whether BAIBA causes muscle from the mice to activate genes associated with exercise to increase the numbers of their mitochondria (the "powerhouses" of the cells), turn fuel into energy, change the structure of the muscle to resemble the effects of exercise training and increase muscle blood supply. Finally, we will investigate whether the exercise mimicking effects of BAIBA on muscle result in improved exercise performance, efficiency and muscle metabolism. Ultimately, this study has the capacity to identify whether BAIBA can mimic the effects of exercise in muscle to improve muscle performance. This is potentially important in situations where exercise/physical performance is impaired or needs to be improved, such as in individuals affected by debilitating muscle wasting diseases, or in sports nutrition. The ability to stimulate aspects of exercise in muscle using BAIBA may also be important for people incapable of exercise training through disability or illness.