Urokinase‐type plasminogen activator and hepatocyte growth factor in muscle regeneration

Abstract

Muscle healing has been shown to be severely impaired in urokinase plasminogen activator-deficient (uPA-/-) mice, and accelerated in plasminogen activator inhibitor-1 (PAI1-/-) mice. The purpose of this study was to test the hypothesis that one mechanism by which uPA regulates muscle repair is through activation of hepatocyte growth factor (HGF). Extensor digitorum longus muscles were injured by cardiotoxin injection and harvested at 1, 3, 5 and 10 days post-injury. As expected, muscles from wild-type mice demonstrated increased expression of HGF following injury. Muscles from uPA-/- mice showed decreased levels of active HGF compared to muscle from wild-type mice, and muscles from PAI1-/- mice showed increased levels of active HGF. Muscles from wild-type mice showed uptake of bromodeoxyuridine into proliferating cell nuclei following injury, with a peak at 5 days post-injury. Muscles from uPA-/- mice showed an impaired proliferative response following injury, and muscles from PAI1-/- mice showed an accelerated proliferative response. The number of MyoD positive cells showed a similar trend, with a peak at 5 days post-injury in muscle of wild-type mice, reduced numbers of MyoD positive cells in muscle of uPA-/- mice compared with muscle of wild-type mice and increased numbers in muscle of PAI1-/- mice. These data indicate that uPA activation of HGF may be a key step in the activation and proliferation of satellite cells and the regulation of muscle regeneration. Supported by the Department of Defense Peer Reviewed Medical Research Program.