Mechanisms of skeletal muscle repair and satellite cell regulation

骨骼肌表现出令人难以置信的复杂性，由许多不同类型的细胞组成，包括肌肉纤维、血管系统、基质和神经细胞。这种细胞的多样性赋予肌肉组织显著的可塑性，并有能力重塑这些细胞成分，以应对不同形式的肌肉收缩。此外，骨骼肌是少数几个成年器官之一，具有在创伤或剧烈肌肉收缩后再生新生组织的非凡能力。由于肌肉纤维是终末分化的(不能进行细胞分裂)，这一过程至少部分是通过肌肉驻留干细胞的活动来完成的，这种干细胞被称为“卫星细胞”(SCs)。干细胞对收缩或肌肉创伤的反应是通过细胞增殖来增强其活性，并最终与现有的肌肉纤维融合，提供能够合成或修复受损肌肉蛋白的细胞核。然而，我们对影响干细胞的因素及其与肌肉生理学的关系的了解还不完全，尤其是在人类肌肉中。 我的研究计划致力于了解支持SC功能的基本机制，从而深入了解骨骼肌的动态平衡和组织重塑。由于SC在很大程度上受其所处环境的影响(被称为SC“生态位”)，本研究的主要目的是剖析这一专门隔间的复杂性。现在人们认识到，肌肉收缩可以通过刺激生长因子(GF)配体的分泌来改变SC生态位的组成，从而触发SC的激活。我们的工作将利用新的蛋白质组学方法来揭示新的GFS和SC表达的未知信号受体的功能。由于骨骼肌的复杂性，我们计划采用系统生物学的方法，重点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调节中的作用。利用骨骼肌微环境作为模型系统，我们的目标是更好地了解干细胞、肌肉纤维和壁龛细胞之间的细胞内在(自分泌)和细胞间(旁分泌)通讯。此外，由于肌肉纤维的收缩在改变SC活动的同时导致肌肉微环境的剧烈扰动，我们的研究将探索支撑这些事件的协同效应。 总而言之，这个研究项目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，从生理学、机械学和系统生物学的角度处理问题，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极好的培训机会。

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.