Plasminogen activator inhibitor-1-mediated regulation of skeletal muscle regeneration

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Skeletal muscle is an exceptional organ that is the physiological motor that gives animals (including humans) the ability to perform a wide range of physical tasks. However, performing these activities can result in skeletal muscle damage: more demanding tasks will lead to a greater amount of damage. As a result, skeletal muscle requires constant repair to maintain its physical capacity. An important aspect of basic muscle biology/physiology is how the tissue responds to damage to induce repair processes, however, the factors regulating skeletal muscle repair following injury are complex and our current understanding is limited. After experiencing muscle damage, a large cellular response, including inflammatory cells and skeletal muscle stem cells (called satellite cells), cleans up and repairs the damaged tissue. This response is heavily influenced by a protein hormone known as plasminogen activator inhibitor (PAI)-1. High concentrations of PAI-1 block the ability of tissues to activate the cellular response, therefore compromising tissue remodeling and repair. Determining how PAI-1 operates, the role it plays in controlling cellular activity and the overall repair process will contribute to greater understanding of the process of skeletal muscle regeneration. The proposed experiments focus on investigating how PAI-1 controls selected downstream proteins that allow inflammatory and satellite cells to function following muscle damage, as well as examining how PAI-1 itself is regulated through assessment of particular hormones related to the control skeletal muscle mass. I hypothesize that: 1) a coordinated pattern of reduced PAI-1 activity, increased protease activity, and increased intracellular signalling in macrophages and satellite cells following damaging resistance exercise will be observed in macrophages and activated satellite cells; and 2) hormones known to limit muscle growth will activate PAI-1 expression and reduce expression/activity of PAI-1’s downstream proteases. Tissues and cells from genetic knockout mice will be studied using a variety of cutting edge techniques and methods. Results demonstrated in the animal experiments will then be replicated and evaluated in a study involving human participants who will perform different exercise modes in order to stimulate the PAI-1 system. This research will answer fundamental questions about previously unexplored interactions between the endocrine system and skeletal muscle, will identify promising areas for future research, and initiate impactful knowledge transfer opportunities.