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

运动调节的肌因子样小分子β-氨基异丁酸是旁分泌信号和运动模拟物吗？

• 批准号: BB/T004231/1
• 负责人: Lee Roberts
• 金额: $ 64.73万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FT004231%2F1
• 关键词: exercise; regulated; myokine; like; small

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.

锻炼是在人的一生中保持健康生活方式的重要组成部分。然而，身体是如何将锻炼的努力转化为改善健康的，目前还不完全清楚。运动需要身体不同器官和组织之间复杂的沟通：PGC-1α蛋白协调身体对运动的一些反应，特别是肌肉。然而，PGC-1pha是如何与肌肉细胞外的其他组织“对话”的，目前尚不清楚。我们之前的研究表明，在运动过程中，PGC-1α会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修饰脂肪细胞。肌肉对运动的反应产生的BAIBA被释放到血液中，并促进其他组织的新陈代谢。与未治疗的小鼠相比，服用BAIBA的小鼠燃烧了更多的卡路里，体重增加更少，葡萄糖代谢更好。我们还发现，血液中BAIBA含量较高的人健康风险指标较低，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已经发现，BAIBA也可能将信息传递回肌肉。在这项拟议的研究中，我们询问BAIBA是否因此有助于肌肉适应运动的方式，从而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。具体地说，本研究将研究BAIBA如何影响调节运动适应的基因和蛋白质，并与运动适应的各个方面相关，包括人体肌肉细胞的燃料代谢、蛋白质代谢、肌肉结构和刺激血管生长。我们将研究给小鼠服用BAIBA是否会改善它们的肌肉做功、使用燃料(脂肪和碳水化合物)和抵抗疲劳的能力。我们还将调查BAIBA是否会使小鼠的肌肉激活与运动相关的基因，以增加它们的线粒体(细胞的“动力库”)的数量，将燃料转化为能量，改变肌肉的结构，使其类似于运动训练的效果，并增加肌肉的血液供应。最后，我们将研究BAIBA对肌肉的运动模拟作用是否会改善运动成绩、效率和肌肉新陈代谢。最终，这项研究有能力确定BAIBA是否可以模仿肌肉锻炼的效果来改善肌肉表现。这在运动/身体表现受损或需要改善的情况下可能很重要，例如在患有衰弱肌肉萎缩疾病的个人，或在运动营养方面。对于因残疾或疾病而无法进行运动训练的人来说，使用BAIBA刺激肌肉运动方面的能力也可能很重要。

项目成果

Metabokines in the regulation of systemic energy metabolism

• DOI: 10.1016/j.coph.2022.102286
• 发表时间: 2022-09-19
• 期刊: CURRENT OPINION IN PHARMACOLOGY
• 影响因子: 4
• 作者: MacCannell, Amanda DV.;Roberts, Lee D.
• 通讯作者: Roberts, Lee D.

The exercise-mediated metabokine Beta-aminoisobutyric acid is an exercise mimetic driving skeletal muscle metabolic and functional adaptation

运动介导的代谢因子β-氨基异丁酸是一种驱动骨骼肌代谢和功能适应的运动模拟物

• DOI: 10.1152/physiol.2023.38.s1.5786418
• 发表时间: 2023
• 期刊: Physiology
• 影响因子: 8.4
• 作者: Daou H

Long-chain ceramides are cell non-autonomous signals linking lipotoxicity to endoplasmic reticulum stress in skeletal muscle.

• DOI: 10.1038/s41467-022-29363-9
• 发表时间: 2022-04-01
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: McNally BD;Ashley DF;Hänschke L;Daou HN;Watt NT;Murfitt SA;MacCannell ADV;Whitehead A;Bowen TS;Sanders FWB;Vacca M;Witte KK;Davies GR;Bauer R;Griffin JL;Roberts LD
• 通讯作者: Roberts LD

Endothelial Piezo1 sustains muscle capillary density and contributes to physical activity.

• DOI: 10.1172/jci141775
• 发表时间: 2022-03-01
• 期刊: The Journal of clinical investigation
• 作者: Bartoli F;Debant M;Chuntharpursat-Bon E;Evans EL;Musialowski KE;Parsonage G;Morley LC;Futers TS;Sukumar P;Bowen TS;Kearney MT;Lichtenstein L;Roberts LD;Beech DJ
• 通讯作者: Beech DJ

Linking the unfolded protein response to bioactive lipid metabolism and signalling in the cell non-autonomous extracellular communication of ER stress.

将未折叠蛋白反应与内质网应激的细胞非自主细胞外通讯中的生物活性脂质代谢和信号传导联系起来。

• DOI: 10.1002/bies.202300029
• 发表时间: 2023
• 期刊: news and reviews in molecular, cellular and developmental biology
• 作者: Watt NT