Adult skeletal muscle possesses remarkable potential for growth in response to mechanical loading; however, many of the cellular and molecular mechanisms involved remain undefined. The hypothesis of this study 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. Compensatory muscle 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 activity of uPA in the PLT muscle. 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-I, 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 muscle hypertrophy. Decreased macrophage accumulation was associated with reduced cell proliferation but did not alter signaling through the mammalian target of rapamycin pathway. These data indicate that uPA and macrophages are required for muscle hypertrophy following synergist ablation.

IntroductionWe hypothesized that cerebral alterations in edema, perfusion, and/or intracranial pressure (ICP) are related to the development of acute mountain sickness (AMS).MethodsTo vary AMS, we manipulated ambient oxygen, barometric pressure, and exercise duration. Thirty‐six subjects were tested before, during and after 8 h exposures in (1) normobaric normoxia (NN; 300 m elevation equivalent); (2) normobaric hypoxia (NH; 4400 m equivalent); and (3) hypobaric hypoxia (HH; 4400 m equivalent). After a passive 15 min ascent, each subject participated in either 10 or 60 min of cycling exercise at 50% of heart rate reserve. We measured tissue absorption and scattering via radio‐frequency near‐infrared spectroscopy (NIRS), optic nerve sheath diameter (ONSD) via ultrasound, and AMS symptoms before, during, and after environmental exposures.ResultsWe observed significant increases in NIRS tissue scattering of 0.35 ± 0.11 cm−1 (P = 0.001) in subjects with AMS (i.e., AMS+), consistent with mildly increased cerebral edema. We also noted a small, but significant increase in total hemoglobin concentrations with AMS+, 3.2 ± 0.8 μmolL−1 (P < 0.0005), consistent with increased cerebral perfusion. No effect of exercise duration was found, nor did we detect differences between NH and HH. ONSD assays documented a small but significant increase in ONSD (0.11 ± 0.02 mm; P < 0.0005) with AMS+, suggesting mildly elevated ICP, as well as further increased ONSD with longer exercise duration (P = 0.005).ConclusionIn AMS+, we found evidence of cerebral edema, elevated cerebral perfusion, and elevated ICP. The observed changes were small but consistent with the reversible nature of AMS.

In this study, we quantified the changes in post-exercise resting heart rate (HRrst) associated with acute mountain sickness (AMS), and compared the effects of hypobaric hypoxia (HH) and normobaric hypoxia (NH) on HRrst. We also examined the modulating roles of exercise duration and exposure time on HRrst. Each subject participated in 2 of 6 conditions: normobaric normoxia (NN), NH, or HH (4 400 m altitude equivalent) combined with either 10 or 60 min of moderate cycling at the beginning of an 8-h exposure. AMS was associated with a 2 bpm higher HRrst than when not sick, after taking into account the ambient environment, exercise duration, and SpO2. In addition, HRrst was elevated in both NH and HH compared to NN with HRrst being 50% higher in HH than in NH. Participating in long duration exercise led to elevated resting HRs (0.8-1.4 bpm higher) compared with short exercise, while short exercise caused a progressive increase in HRrst over the exposure period in both NH and HH (0.77-1.2 bpm/h of exposure). This data suggests that AMS, NH, HH, exercise duration, time of exposure, and SpO2 have independent effects on HRrst. It further suggests that hypobaria exerts its own effect on HRrst in hypoxia. Thus NH and HH may not be interchangeable environments.