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: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=680872
• 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，并由许多不同的细胞类型组成，包括肌肉纤维，脉管系统，基质和神经细胞。这种细胞多重性赋予肌肉组织具有显着的可塑性，并且能够重塑这些细胞的能力是响应各种形式的肌肉收缩而构成的。此外，骨骼肌是少数具有显着的成年器官之一，具有在创伤或剧烈的肌肉收缩后重生从头组织的能力。由于肌肉纤维被极端分化（并且无法细胞分裂），因此至少部分地通过称为“卫星细胞”（SCS）的肌肉居民干细胞的活性来完成此过程。 SC通过通过细胞增殖增强其活性，并最终与现有的肌肉纤维融合，以供应能够合成或修复受损坏的肌肉蛋白的核，从而对合同或肌肌反应。但是，我们对影响SC的因素及其与肌肉生理的关系的理解是不完整的，尤其是在人类肌肉中。由于SC在很大程度上受其居住环境的影响（称为SC“利基”），因此该研究的主要目标是剖析该专业隔间的复杂性。现在认为，肌肉收缩可以通过刺激触发SCS激活的生长因子（GF）配体的分泌（GF）的分泌来改变SC生态位的组成。我们的工作将利用新型的蛋白质组学方法来揭示SC表达的新GFS和未识别的信号受体的功能。由于骨骼肌的复杂性，我们计划采用一种系统生物学方法，重点是理解SC调节中骨骼肌的非小细胞成分（例如基质细胞，脉管系统，神经系统）的贡献。我们利用骨骼肌微环境作为模型系统，旨在对SCS，肌肉纤维和小细胞之间的细胞内在（自分泌）和细胞对细胞（旁分泌）通信有更深入的了解。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，同时改变了SC活动，因此我们的研究将探讨这些事件的协同作用。通过利用许多尖端技术，并从生理，机械和系统生物学角度来解决问题，我们的结果将与广泛的受众相关，并将为高素质的人员提供出色的培训机会。 *****