Cellular mechanisms underlying temporal changes in skeletal muscle protein synthesis and breakdown during chronic β-adrenoceptor stimulation in mice

Chronic stimulation of beta-adrenoceptors with beta-adrenoceptor agonists (beta-agonists) can induce substantial skeletal muscle hypertrophy, but the mechanisms mediating this muscle growth have yet to be elucidated. We investigated whether chronic beta-adrenoceptor stimulation in mice with the beta-agonist formoterol alters the muscle anabolic response following beta-adrenoceptor stimulation. Twelve-week-old C57BL/6 mice were treated for up to 28 days with a once-daily injection of either saline (control, n = 9) or formoterol (100 mu g kg-1; n = 9). Rates of muscle protein synthesis were assessed at either 1, 7 or 28 days of treatment, 6 h after injection. Protein synthesis rates were higher in formoterol-treated mice at day 7 (similar to 1.5-fold, P < 0.05), but not at day 1 or 28. The increased muscle protein synthesis was associated with increased phosphorylation of S6K1 (r = 0.49, P < 0.01). Formoterol treatment acutely reduced maximal calpain activity by similar to 25% (P < 0.05) but did not affect atrogin-1 protein levels and proteasome-mediated proteolytic activity, despite significantly enhanced phosphorylation of Akt (P < 0.05). Formoterol increased CREB phosphorylation by similar to 30% (P < 0.05) and PPAR gamma coactivator-1 alpha (PGC-1 alpha) by 11-fold (P < 0.05) on day 1 only. These observations identify that formoterol treatment induces muscle anabolism, by reducing calpain activity and by enhancing protein synthesis via increased PI-3 kinase/Akt signalling.