Mechanisms underlying the regulation of human skeletal muscle protein turnover by omega-3 fatty acids.

骨骼肌是一种重要的器官，是全身新陈代谢的主要贡献者，为运动和呼吸提供必要的力量。骨骼肌的大小是由肌肉蛋白质合成速率(MPS)和肌肉蛋白质分解速率(MPB)的变化支撑的。当MPS超过MPS时，骨骼肌将生长(肥大)，当MPS超过MPS时，骨骼肌将缩小(萎缩)。MPS和MPB都是利用线粒体中产生的能量进行耗能的过程。然而，整合调控MPS、MPB和线粒体能量产生的细胞和分子机制在很大程度上仍不清楚。已知的是，MPS和MPB对收缩活动和营养敏感。阻力运动和蛋白质喂养会增加MPS，反复进行阻力运动和蛋白质喂养会导致骨骼肌肥大。耐力运动还会刺激MPS，随着时间的推移，会导致线粒体蛋白质含量增加。相反，我们最近表明，肌肉停用一段时间会减少由线粒体蛋白质含量下降引发的MPS，并减少骨骼肌萎缩，即使蛋白质摄入量超过推荐的饮食摄入量也是如此。有趣的是，我们最近的工作表明，提供omega-3脂肪酸，通常被称为鱼油，可以防止MPS、线粒体蛋白质含量和骨骼肌大小在肌肉停用期间因不明机制而下降(S)。我的研究计划的主要目标是在我之前工作的基础上，了解omega-3脂肪酸对女性和男性骨骼肌的合成代谢影响的生物学机制。这项工作将使用一系列的生化技术，包括骨骼肌蛋白质的同位素标记，线粒体呼吸动力学的测量，以及对基因表达和蛋白激酶活性变化的评估。具体地说，我将利用锻炼和肌肉停用来扰乱摄入omega-3脂肪酸一段时间后MPS和MPB的速率，并探测合成信号分子的变化，以精确定位omega-3脂肪酸在骨骼肌中的机械作用。这项探索基金中提出的工作将对加拿大的研究和创新产生一些影响。首先，所获得的知识将提供关于omega-3脂肪酸暴露如何影响人类骨骼肌质量调节的基本的、机械性的理解。反过来，这一新知识可能被应用于开发治疗方法，以减少肌肉损耗，增加肌肉大小，并与人类代谢功能障碍相关的疾病作斗争。最后，这项工作计划将作为许多HQP的培训工具，这些HQP将获得准备部署在学术界或私营部门的独特的跨学科技能。

Skeletal muscle is a critical organ serving as a major contributor to whole-body metabolism and provides the necessary force to support movement and breathing. The size of skeletal muscle is underpinned by changes in rates of muscle protein synthesis (MPS) and rates of muscle protein breakdown (MPB). When MPS exceeds MPB skeletal muscle will grow (hypertrophy) and when MPB exceeds MPS skeletal muscle will reduce in size (atrophy). Both MPS and MPB are energetically expensive processes utilizing energy produced in the mitochondria. However, the cellular and molecular mechanisms that integrate the regulation of MPS, MPB, and mitochondrial energy production in humans remains largely unknown. What is known is that MPS and MPB are sensitive to contractile activity and nutrition. Resistance exercise and protein feeding increase MPS with repeated bouts of resistance exercise and protein feeding leading to skeletal muscle hypertrophy. Endurance exercise will also stimulate MPS and over time lead to increased mitochondrial protein content. Conversely, we have recently shown that a period of muscle-disuse reduces MPS initiating in a decline in mitochondrial protein content, and skeletal muscle atrophy even when protein intakes are above the recommended dietary allowance. Intriguingly, our recent work has shown that the provision of omega-3 fatty acids, commonly known as fish oils, protect against declines in rates of MPS, mitochondrial protein content, and skeletal muscle size during a period of muscle-disuse by unidentified mechanism(s). The overarching aim of my research program is to build on my previous work to understand the biological mechanisms that mediate the anabolic influence of omega-3 fatty acids on skeletal muscle in women and men. This work will employ a range of biochemical techniques including isotopic labelling of skeletal muscle proteins, measurement of mitochondrial respiration kinetics, and assessment of changes in gene expression and protein kinase activity. Specifically, I will utilize exercise and muscle-disuse to disrupt rates of MPS, and MPB following a period of omega-3 fatty acid feeding and probe for changes in anabolic signalling molecules to pinpoint mechanistic actions of omega-3 fatty acids in skeletal muscle. The work proposed in this Discovery Grant will have a number of implications for Canadian research and innovation. Primarily, the knowledge gained will deliver a basic, mechanistic understanding of how omega-3 fatty acid exposure influences the regulation of human skeletal muscle mass. In turn, this new knowledge may be applied in the development of therapies to reduce muscle wasting, enhance muscle size, and combat disorders associated with metabolic dysfunction in humans. Lastly, this program of work will serve as a training vehicle for a number of HQP that will acquire a unique and cross-disciplinary skillset ready to be deployed in either the academic or private sector.