Mechanisms of skeletal muscle repair and satellite cell regulation

骨骼肌修复和卫星细胞调节机制

• 批准号: RGPIN-2016-05747
• 负责人: Johnston, Adam
• 金额: $ 1.82万
• 依托单位: University of Prince Edward Island
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=709946
• 关键词: Mechanisms; skeletal; muscle; repair; satellite

Skeletal muscle displays incredible complexity and is comprised of many diverse cell types including muscle fibers, vasculature, stroma and neural cells. This cellular multiplicity endows muscle tissue with significant plasticity and the ability to remodel these cellular constituents in response to varied forms of muscle contraction. Additionally, skeletal muscle is one of the few adult organs with the remarkable ability to regenerate de novo tissue following trauma or strenuous muscle contraction. As muscle fibers are terminally differentiated (and not capable of cell division), this process is accomplished, at least in part, by the activity of muscle resident stem cells termed “satellite cells” (SCs). SCs respond to contraction or myotrauma by enhancing their activity through cell proliferation and ultimately fuse with existing muscle fibres to supply nuclei capable of synthesizing or repairing damaged muscle proteins. However, our understanding of the factors that influence SCs and their relationship to muscle physiology is incomplete, especially in human muscle. My research program strives to gain an understanding of the fundamental mechanisms that underpin SC function to lend insight into skeletal muscle homeostasis, and tissue remodeling. Since SCs are largely influenced by the environment in which they reside (known as the SC “niche”) a major goal of this research is to dissect the complexities of this specialized compartment. It is now appreciated that muscle contraction can alter the composition of the SC niche by stimulating the secretion of growth factor (GF) ligands that trigger the activation of SCs. Our work will utilize novel proteomic methods to uncover the function of new GFs and unidentified signaling receptors expressed by SC. Due to the complexity of skeletal muscle, we plan to take a systems biology approach with a focus on understanding the contribution of the non-myocellular components (e.g. stromal cells, vasculature, nervous system) of skeletal muscle in SC regulation. Utilizing the skeletal muscle microenvironment as a model system, we aim to gain a greater understanding of the cell intrinsic (autocrine) and cell-to-cell (paracrine) communication between SCs, muscle fibres and niche cells. Moreover, since contraction of muscle fibers induces acute perturbations to this muscle microenvironment while altering SC activity, our research will probe the synergies that underpin these events. Collectively, the information generated from this research program has the potential to impact our fundamental understanding of human SC regulation, muscle remodeling and skeletal muscle physiology. By utilizing many cutting-edge techniques and approaching questions from physiological, mechanistic, and systems biology angles our results will be relevant to a wide audience and will provide excellent training opportunities for highly qualified personnel.

骨骼肌表现出令人难以置信的复杂性，由许多不同的细胞类型组成，包括肌纤维、脉管系统、基质和神经细胞。 这种细胞多样性赋予肌肉组织显著的可塑性和重塑这些细胞成分的能力，以响应各种形式的肌肉收缩。 此外，骨骼肌是在创伤或剧烈肌肉收缩后具有显著的从头组织再生能力的少数成人器官之一。 由于肌纤维是终末分化的（并且不能进行细胞分裂），该过程至少部分地通过称为“卫星细胞”（SC）的肌肉驻留干细胞的活性来完成。 SC通过细胞增殖增强其活性来响应收缩或肌肉创伤，并最终与现有的肌纤维融合，以提供能够合成或修复受损肌肉蛋白的细胞核。 然而，我们对影响SC的因素及其与肌肉生理学的关系的理解是不完整的，特别是在人类肌肉中。 我的研究项目致力于了解支持SC功能的基本机制，以深入了解骨骼肌的稳态和组织重塑。 由于SC在很大程度上受到他们居住的环境（称为SC“生态位”）的影响，本研究的一个主要目标是剖析这一特殊的隔间的复杂性。 现在认识到，肌肉收缩可以通过刺激触发SC活化的生长因子（GF）配体的分泌来改变SC小生境的组成。我们的工作将利用新的蛋白质组学方法来揭示新的GFs和未知的信号受体表达的SC的功能。由于骨骼肌的复杂性，我们计划采取系统生物学的方法，重点是了解骨骼肌的非肌细胞成分（如基质细胞，血管系统，神经系统）在SC调节的贡献。 利用骨骼肌微环境作为模型系统，我们的目标是获得更好的理解SC，肌纤维和龛细胞之间的细胞内（自分泌）和细胞间（旁分泌）的通信。此外，由于肌肉纤维的收缩会引起这种肌肉微环境的急性扰动，同时改变SC的活性，我们的研究将探讨这些事件的协同作用。 总的来说，从这项研究计划产生的信息有可能影响我们对人类SC调节，肌肉重塑和骨骼肌生理学的基本理解。 通过利用许多尖端技术，并从生理学，机械学和系统生物学角度接近问题，我们的结果将与广泛的受众相关，并将为高素质的人才提供良好的培训机会。