Adult skeletal muscle possesses remarkable potential for growth in response to mechanical loading;​ however, many of the cellular and molecular mechanisms involved remain unclear. While the intracellular mechanisms controlling hypertrophy have been well-studied, the role of extracellular processes and non-muscle cells that may also contribute to hypertrophy have not been defined. Skeletal muscle hypertrophy has been associated with inflammation, but the necessity, function, or regulation of this inflammation has not been examined. The hypothesis of this dissertation was that the extracellular serine protease, urokinase-type plasminogen activator (uPA), is required for muscle hypertrophy, in part by promoting macrophage accumulation in muscle subjected to increased mechanical loading, and that uPA stimulates macrophage proliferation.

Compensatory hypertrophy was induced in mouse plantaris (PLT) muscles by surgical ablation of synergist muscles. Following synergist ablation, PLT muscles in wild-type mice demonstrated edema and infiltration of neutrophils and macrophages but an absence of overt muscle fiber damage. Sham procedures resulted in no edema or accumulation of inflammatory cells. In addition, synergist ablation was associated with a large increase in uPA activity in the PLT. uPA null mice demonstrated complete abrogation of compensatory hypertrophy associated with reduced macrophage accumulation, indicating that uPA is required for hypertrophy. Macrophages isolated from wild-type PLT muscle during compensatory hypertrophy expressed uPA and IGF-1, both of which may contribute to hypertrophy. To determine whether macrophages are required for muscle hypertrophy, clodronate liposomes were administered to deplete macrophages in wild-type mice;​ this resulted in reduced hypertrophy. Decreased macrophage accumulation was associated with reduced cell proliferation but did not alter signaling through the mammalian target of rapamycin pathway.

To determine the role of uPA in macrophage proliferation, cultured macrophages from wild-type mice were exposed to various doses of uPA and its inhibitor, PAI-1. Although overridden by low statistical power, results suggest that exogenous uPA may increase macrophage proliferation. Furthermore, the non-proteolytic domain of uPA did not stimulate proliferation, and uPA-stimulated macrophage proliferation was impaired by blocking uPA's proteolytic domain with PAI-1, suggesting that macrophage proliferation is mediated by uPA's proteolytic functions. In conclusion, this dissertation suggests that macrophages and uPA are required for skeletal muscle hypertrophy, and uPA-dependent hypertrophy may be mediated by uPA's proteolytic functions. In addition, uPA may stimulate macrophage proliferation in vitro, and this may also be the result of a protease-dependent mechanism.