Grant: Discovery Grants Program - Individual

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.