Grant: Discovery Grants Program - Individual

Skeletal muscle is an essential organ system for movement, energy homeostasis, and metabolic function. However, the regulation of its mechanical properties and morphology are not completely understood. In response to the habitual patterns of neural activation which innervate it, the expression of muscle phenotype varies, allowing the tissue characteristics of each muscle to match the biomechanical and metabolic needs of the organism. When activated, the Ca2+-dependent control of the acute force response is coupled to the cellular machinery that regulates tissue homeostasis and plasticity. Therefore, mechanisms that influence intracellular Ca2+ homeostasis are of interest to both the modulation of contractile function and the intracellular signalling processes which regulates muscle phenotype. Pannexins are a recently discovered family of glycoproteins that form large-pore membrane channels in many tissues and are implicated in a range of cellular functions. In particular, there is emerging evidence that pannexins regulate communication between the intracellular and extracellular environments and facilitate the movement of ions and small molecules, including ATP. In skeletal muscle, pannexins may therefore be implicated in the autocrine and paracrine signalling pathways which form the basis of the tissue's mechanosensitivity and plasticity. Recently, the predominant isoform in skeletal muscle, PANX1, has been linked to the modulation of excitation-contraction and excitation-transcription coupling processes. Briefly, the permeability of PANX1 channels is stimulated by sarcolemmal depolarization and facilitates the efflux of ATP from the cell, which activates extracellular purinergic receptors and initiates various downstream responses, including the release of sequestered Ca2+ stores. To test this putative mechanism, we will investigate how controlling PANX1 expression and activity modulates contractile performance and the expression of fast and slow muscle phenotypes, both of which are Ca2+-dependent processes. Our recent pilot data is consistent with the hypothesis that PANX1 channels and extracellular purinergic receptors may contribute to the modulation of contractile force produce via transient increases in intracellular Ca2+ homeostasis following muscle activation. The biological role of pannexins in skeletal muscle have not been widely studied in models which focus on intact tissues, which represents a gap in knowledge and provides an excellent opportunity for discovery and the production of novel findings. In the proposed research program, we have outlined a hypothesis-driven experimental plan which utilizes our expertise in rodent models of skeletal muscle physiology and established knowledge of pannexin biology and skeletal muscle plasticity. The anticipated outcomes of the proposed research will contribute to our understanding of the adaptive responses to various stimuli, including habitual physical activity and hypokinesia.