Dose-dependent separation of the hypertrophic and myotoxic effects of the β2-adrenergic receptor agonist clenbuterol in rat striated muscles

Muscle growth in response to large doses (milligrams per kilogram) of beta(2)-adrenergic receptor agonists has been reported consistently. However, such doses may also induce myocyte death in the heart and skeletal muscles and hence may not be safe doses for humans. We report the hypertrophic and myotoxic effects of different doses of clenbuterol. Rats were infused with clenbuterol (range, 1 mu g to 1 mg.kg(-1)) for 14 days. Muscle protein content, myofiber cross-sectional area, and myocyte death were then investigated. Infusions of >= 10 mu g.kg(-1).d(-1) of clenbuterol significantly (P < 0.05) increased the protein content of the heart (12%-15%), soleus (12%), plantaris (118%-29%), and tibialis anterior (111%-22%) muscles, with concomitant myofiber hypertrophy. Larger doses (100 mu g or 1 mg) induced significant (P < 0.05) myocyte death in the soleus (peak 0.2 +/- 0.1% apoptosis), diaphragm (peak 0.15 +/- 0.1% apoptosis), and plantaris (peak 0.3 +/- 0.05% necrosis), and significantly increased the area fraction of Collagen in the myocardium. These data show that the low dose of 10 mu g.kg(-1).d(-1) can be used in rats to investigate the anabolic effects of clenbuterol in the absence of myocyte death.