Thesis (Ph.D.)--University of Washington, 2014Skeletal muscle has significant regenerative capacity, which is impaired with muscular dystrophy and aging. Muscle function and repair requires the involvement of several cellular compartments and molecular interactions. With disease cellular responses are influenced by the alteration of signaling pathways that are involved in the normal process of muscle regeneration. Disruptions in regenerative signaling coincide with the activation of pathways responsible for tissue pathology. Therefore, the cellular and molecular axis of muscle regeneration follows a strict program that when interrupted by disease, cannot sustain repair and results in muscle degeneration. The cellular compartments of the skeletal muscle respond as a collective to repair damage. Each cellular population is influenced by distinct pathways and cellular interactions. In the absence of disease, the process of regeneration is mediated by satellite cells, endothelial cells and collagen producing cells to respond to injury and regenerate muscle fibers, vessels, and reconstitute damaged connective tissue respectively. With disease, signaling pathways that influence cellular responses to injury are altered. As described in this dissertation, we discovered Sphingosine-1-Phosphate (S1P) and Platelet Derived Growth Factor Receptor-α (PDGFRα) are two signaling pathways with opposing effects in muscular dystrophy. With muscular dystrophy, the accumulation of fibrosis perturbs the regenerative response. Therefore, we hypothesis that alterations in the muscle's repair processes contribute to pathogenesis; pro-regenerative pathways (such as S1P) diminish as pro-fibrotic pathways (such as PDGFRα) remain active. Understanding the cellular crosstalk and both processes of degeneration and regeneration are crucial for the development of therapies that can reduce muscle pathology and promote repair. Herein, we explore the axis of molecular signaling and cellular responses that influence muscle regeneration during injury and wasting. Such a holistic approach is necessary for continuing our advance in treating muscle wasting diseases. Our main findings support our hypothesis that regeneration and degeneration are intimately linked. Two cell populations affected by muscular dystrophy (endothelial cells and satellite cells) are diverse resident cells involved in S1P signaling of the muscle. In contrast, collagen producing cells are activated by PDGFRα to promote fibrosis and perturb regeneration. In summary, our findings, support the development of combinatory therapies that target specific pathways, such as S1P and PDGFRα, to promote regenerative signaling while negating the effects of degenerative signaling on muscle repair. Despite the potential of such cellular and molecular strategies, significant barriers exit in the culture and politics of science that I will discuss in the closing commentary. Here I will describe the current scientific crisis, which in my own opinion extends not only from a decline in funding, but abuse and misuse of resources has rampant for years. In addition the structure of scientific training and funding has compounded this crisis, as more PhD's continue to be trained despite the recognizable and ongoing decline in scientific employment. Therefore, in the past two decades, the field of biological science has adapted a policy analogous to our government's stance on global warming; ignore the immanent catastrophe. This will not come in the form of rising oceans or temperatures, but stagnation of discoveries and treatment for diseases. This calamity can be averted if we, as a community, divert from politics and personal gain, but instead focus our efforts on conducting meaningful science with the public's best interests in mind
