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

J Physiol. 2010 Dec 1;588(Pt 23):4811-23. doi: 10.1113/jphysiol.2010.196725. Epub 2010 Oct 11.

Abstract

Chronic stimulation of β-adrenoceptors with β-adrenoceptor agonists (β-agonists) can induce substantial skeletal muscle hypertrophy, but the mechanisms mediating this muscle growth have yet to be elucidated. We investigated whether chronic β-adrenoceptor stimulation in mice with the β-agonist formoterol alters the muscle anabolic response following β-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 μg 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 (∼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 ∼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 ∼30% (P < 0.05) and PPARγ coactivator-1α (PGC-1α) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Agonists / pharmacology*
  • Animals
  • Calpain / genetics
  • Calpain / metabolism
  • Drug Administration Schedule
  • Ethanolamines / administration & dosage
  • Ethanolamines / pharmacology*
  • Formoterol Fumarate
  • Gene Expression Regulation / drug effects*
  • Gene Expression Regulation / physiology
  • Mice
  • Mice, Inbred C57BL
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Muscle, Skeletal / metabolism*
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism
  • Receptors, Adrenergic, beta / physiology
  • Ribosomal Protein S6 Kinases, 70-kDa / genetics
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Signal Transduction
  • Ubiquitin / genetics
  • Ubiquitin / metabolism

Substances

  • Adrenergic beta-Agonists
  • Ethanolamines
  • Muscle Proteins
  • Receptors, Adrenergic, beta
  • Ubiquitin
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Calpain
  • Proteasome Endopeptidase Complex
  • Formoterol Fumarate