Macrophages are required for skeletal muscle growth in a synergist ablation model of hypertrophy

Previous studies have demonstrated that macrophages and urokinase plasminogen activator (uPA) are required for effective skeletal muscle repair after injury. The purpose of this study was to investigate whether macrophages and uPA are required for hypertrophy. Hypertrophy was induced in wild‐type (WT) and uPA‐null mouse plantaris muscles via synergist ablation (SA). Another group of WT mice were injected with clodronate liposomes to deplete macrophages following SA. Muscles were harvested at 1, 3, 5 and 14 d post‐SA. Muscle mass increased by 100% and total protein by 74% 14 d post‐SA in WT mice. SA resulted in edema at 1 and 3 d and accumulation of macrophages at 3 and 5 d. Macrophage accumulation occurred between fibers with rare incidence of overt fiber necrosis. Results of sham operations, which produced little edema or inflammatory cell accumulation, suggest these changes were a result of increased mechanical loading rather than surgery. Treatment with clodronate decreased macrophages following SA. Furthermore, treated mice demonstrated reduced hypertrophy compared with non‐treated mice following SA. uPA activity was increased in WT muscles after SA, and macrophages were a source of uPA in these muscles. uPA‐null muscles had decreased macrophages and hypertrophy. These results suggest that macrophage accumulation is required for this model of hypertrophy, and uPA plays an important role in hypertrophy. Support for this project came from the Department of Defense.