Mechanisms of human skeletal muscle disuse atrophy

人体骨骼肌废用性萎缩的机制

• 批准号: RGPIN-2018-04113
• 负责人: ChurchwardVenne, Tyler
• 金额: $ 1.75万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=647734
• 关键词: Mechanisms; human; skeletal; muscle; disuse

Skeletal muscle is a unique tissue with a tremendous capacity to modify its size and functional characteristics in response to changes in physical activity. Periods of sedentary behavior and muscle disuse (e.g., due to limb casting or bed rest) lead to a decline in skeletal muscle mass, also known as “disuse muscle atrophy”. Muscle atrophy is a non-pathological event characterized by a reduction in muscle fibre size resulting from a loss of muscle protein content. Muscle loss will likely affect every person at some point during their lifetime and has negative consequences including reductions in strength, the onset of insulin resistance, and body fat-mass accumulation. Despite these negative consequences, the processes and mechanisms that cause disuse-related muscle atrophy in humans remain unclear. The LONG TERM OBJECTIVE of my research program is to understand the metabolic and molecular regulation of human muscle protein metabolism in response to stimuli that promote skeletal muscle loss (e.g., muscle disuse), maintenance (e.g., physical activity, nutritional intake) and/or growth (e.g., resistance exercise). Over the next five-years, my laboratory will address two short-term research objectives that will contribute to my long-term research objective. The first SHORT-TERM OBJECTIVE is to develop a greater understanding of the metabolic and mechanistic causes of disuse-induced skeletal muscle atrophy in humans. The maintenance of skeletal muscle mass is dependent on the regulated balance between muscle protein synthesis (MPS) and muscle protein breakdown (MPB). Under atrophy conditions, the rate of MPB exceeds the rate of MPS resulting in net loss of muscle protein. However, the contribution of changes in MPS and MPB to disuse atrophy is unknown, and may differ to varying extents at different time-points during disuse and between different muscles in the body. The second SHORT-TERM OBJECTIVE is to identify the metabolic and molecular processes that facilitate skeletal muscle growth in humans. Muscle atrophy can be reversed with physical activity and exercise. Resistance exercise arguably offers the most effective strategy to increase skeletal muscle mass and strength. Muscle growth occurs when MPS exceeds MPB resulting in an increase of muscle proteins, and eventually muscle growth. However, the metabolic and molecular events that promote skeletal muscle growth after disuse have not been explored in humans. The results from this research will enhance our fundamental understanding of the mechanisms responsible for disuse-induced skeletal muscle atrophy, and provide insight into how resistance exercise facilitates muscle growth in previously atrophied and non-atrophied muscle. This knowledge will contribute to the development of effective countermeasures for the prevention and rehabilitation of disuse skeletal muscle atrophy.**********************

骨骼肌是一种独特的组织，它具有巨大的能力来改变其大小和功能特征，以响应身体活动的变化。长期的久坐行为和肌肉废用（例如，由于肢体移位或卧床休息）会导致骨骼肌质量下降，也称为“废用肌萎缩”。肌肉萎缩是一种非病理性事件，其特征是肌肉蛋白质含量的减少导致肌肉纤维大小的减少。肌肉损失可能会影响到每个人一生中的某个时刻，并产生负面后果，包括力量下降、胰岛素抵抗的发生和身体脂肪量的积累。尽管有这些负面影响，但导致人类废用相关肌肉萎缩的过程和机制仍不清楚。我的研究项目的长期目标是了解人体肌肉蛋白质代谢的代谢和分子调控，以响应促进骨骼肌损失（例如，肌肉废用），维持（例如，体育活动，营养摄入）和/或生长（例如，阻力运动）的刺激。在接下来的五年里，我的实验室将解决两个短期研究目标，这将有助于我的长期研究目标。第一个短期目标是进一步了解废用诱导的人类骨骼肌萎缩的代谢和机制原因。骨骼肌质量的维持依赖于肌肉蛋白合成（MPS）和肌肉蛋白分解（MPB）之间的调节平衡。在萎缩条件下，MPB的速率超过MPS的速率，导致肌肉蛋白质的净损失。然而，MPS和MPB的变化对废用性萎缩的贡献尚不清楚，并且在废用期间的不同时间点和体内不同肌肉之间可能存在不同程度的差异。第二个短期目标是确定促进人类骨骼肌生长的代谢和分子过程。肌肉萎缩可以通过体育活动和锻炼来逆转。阻力运动可以说是增加骨骼肌质量和力量的最有效的策略。肌肉生长发生在MPS超过MPB时，导致肌肉蛋白质增加，最终肌肉生长。然而，代谢和分子事件促进骨骼肌废弃后生长的人类尚未探索。这项研究的结果将增强我们对废用诱导的骨骼肌萎缩机制的基本理解，并为阻力运动如何促进先前萎缩和非萎缩肌肉的肌肉生长提供见解。这一知识将有助于制定预防和康复废用骨骼肌萎缩的有效对策。**********************