Hepatocyte growth factor affects satellite cell activation and differentiation in regenerating skeletal muscle

Hepatocyte growth factor (HGF) is the only known growth factor that activat es quiescent satellite cells in skeletal muscle. We hypothesized that local delivery of HGF may enhance regeneration after trauma by increasing the nu mber of myoblasts available for restoring normal tissue architecture. Injec tion of HGF into muscle at the time of injury increases myoblast number but does not enhance tissue repair as determined using quantitative histologic al analyses. Rather; depending on the dose and the timing of HGF administra tion relative to the injury, regeneration can be inhibited. The greatest in hibitory effect is observed when HGF is administered on the day of injury a nd continued for 3 days, corresponding to the time when satellite cell acti vation, proliferation, and early differentiation normally occur. To establi sh a mechanism for this inhibition, we show that HGF can act directly on pr imary muscle cells to block differentiation. These results demonstrate that 1) exogenous HGF synergizes with factors in damaged muscle to increase myo blast number, 2) regeneration is not regulated solely by myoblast number, a nd 3) HGF inhibits muscle differentiation both in vitro and in vivo.