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

骨骼肌是一个重要的器官，作为全身代谢的主要贡献者，并提供必要的力量来支持运动和呼吸。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）的变化所决定的。当MPS超过MPB时，骨骼肌会生长（肥大），当MPB超过MPS时，骨骼肌会变小（萎缩）。MPS和MPB都是能量昂贵的过程，利用线粒体产生的能量。然而，人类MPS、MPB和线粒体能量产生调控的细胞和分子机制在很大程度上仍然未知。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增加MPS，反复进行阻力运动和蛋白质喂养导致骨骼肌肥大。耐力运动也会刺激MPS，并随着时间的推移导致线粒体蛋白质含量的增加。相反，我们最近的研究表明，一段时间的肌肉不使用会减少MPS，导致线粒体蛋白质含量下降，即使蛋白质摄入量高于推荐的膳食摄入量，骨骼肌也会萎缩。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率下降，线粒体蛋白含量下降，骨骼肌大小在肌肉停止使用期间，机制不明。我的研究计划的总体目标是在我以前的工作的基础上，了解调节omega-3脂肪酸对女性和男性骨骼肌合成代谢影响的生物学机制。这项工作将采用一系列生化技术，包括骨骼肌蛋白的同位素标记，线粒体呼吸动力学的测量，以及基因表达和蛋白激酶活性变化的评估。具体来说，我将利用锻炼和肌肉废用来破坏进食一段时间的omega-3脂肪酸后MPS和MPB的速率，并探测合成代谢信号分子的变化，以确定omega-3脂肪酸在骨骼肌中的机制作用。这项发现基金提出的工作将对加拿大的研究和创新产生许多影响。首先，所获得的知识将提供对omega-3脂肪酸如何影响人体骨骼肌质量调节的基本机制理解。反过来，这一新知识可能应用于治疗的发展，以减少肌肉萎缩，增加肌肉尺寸，并与代谢功能障碍相关的疾病在人类中。最后，这一工作计划将作为一批HQP的培训工具，这些HQP将获得一套独特的跨学科技能，准备在学术或私营部门部署。

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.