Regulation of Skeletal Muscle Regeneration By Macrophages and the Urokinase-Type Plasminogen Activator
- Paper number
IAC-07-A1.2.07
- Author
Mr. Scott Bryer, University of Illinois at Chicago, United States
- Year
2007
- Abstract
Spaceflight is associated with muscle atrophy and return to weight bearing is associated with muscle injury. Urokinase plasminogen activator (uPA) is expressed by both macrophages and satellite cells, both of which are important for muscle remodeling. Mice deficient in uPA demonstrate severely impaired skeletal muscle regeneration associated with decreased accumulation of macrophages. The purpose of this study was to better understand the role of uPA and the function of macrophages in muscle remodeling, which may provide a target for therapeutic and medical interventions. Although macrophages are thought to promote tissue repair, the molecular mechanisms involved remain to be elucidated. The guiding hypothesis of the current series of experiments was that skeletal muscle regeneration requires macrophage accumulation and their expression of components of the plasminogen activator system. Results suggest uPA can act independently of its specific receptor, uPAR, since macrophage accumulation and subsequent muscle regeneration was not impaired following injury in uPAR null mice in vivo. Additional in vitro experiments demonstrated that uPA was required for macrophage chemotaxis independent of uPAR. Adhesion, phagocytosis and expression of selected growth factors and cytokines were not different between macrophages from wild-type (WT) and uPA null mice. uPA null mice demonstrated impaired macrophage accumulation and muscle regeneration. Intramuscular injection of exogenous uPA to injured muscle in uPA null mice restored macrophage accumulation and muscle regeneration. Specific depletion of macrophages using clodronate-liposomes resulted in impaired muscle regeneration, mimicking the healing response in uPA null mice. The transfer of WT bone marrow cells to uPA null mice rescued macrophage accumulation and restored muscle regeneration. These results indicate that macrophage-derived uPA is necessary for chemotaxis of macrophages and for efficient muscle regeneration, and as such, may represent a therapeutic target for enhancing macrophage chemotaxis and muscle regeneration following injury or atrophy associated with space exploration. I verify that I am a US citizen and a full-time graduate student majoring in a field related to the IAF research topics. The abstract submitted is original and has not been presented at another meeting.
- Abstract document