title: Systemic administration of beta2-adrenoceptor agonists, formoterol and salmeterol, elicit skeletal muscle hypertrophy in rats at micromolar doses.
abstract: beta(2)-Adrenoceptor agonists provide a potential therapy for muscle wasting and weakness, but their use may be limited by adverse effects on the heart, mediated in part, by beta(1)-adrenoceptor activation. Two beta(2)-agonists, formoterol and salmeterol, are approved for treating asthma and have an extended duration of action and increased safety, associated with greater beta(2)-adrenoceptor selectivity. The pharmacological profiles of formoterol and salmeterol and their effects on skeletal and cardiac muscle mass were investigated in 12-week-old, male F344 rats. Formoterol and salmeterol were each administered via daily i.p. injection at one of seven doses (ranging from 1 to 2,000 microg kg(-1) day(-1)), for 4 weeks. Rats were anaesthetised and the EDL and soleus muscles and the heart were excised and weighed. Dose-response curves were constructed based on skeletal and cardiac muscle hypertrophy. Formoterol was more potent than salmeterol, with a significantly lower ED(50) in EDL muscles (1 and 130 microg kg(-1) day(-1), P <0.05), whereas salmeterol had greater intrinsic activity than formoterol in both EDL and soleus muscles (12% greater hypertrophy than formoterol). The drugs had similar potency and intrinsic activity in the heart, with a smaller leftward shift for formoterol than seen in skeletal muscle. A dose of 25 microg kg(-1) day(-1) of formoterol elicited greater EDL and soleus hypertrophy than salmeterol, but resulted in similar beta-adrenoceptor downregulation. These results show that doses as low as 1 microg kg(-1) day(-1) of formoterol can elicit significant muscle hypertrophy with minimal cardiac hypertrophy and provide important information regarding the potential therapeutic use of formoterol and salmeterol for muscle wasting.
authors.affiliation: Basic and Clinical Myology Laboratory, Department of Physiology, The University of Melbourne, Grattan Street, Victoria 3010, Australia.
authors.forename: James G
authors.initials: JG
authors.lastname: Ryall
authors.forename: Martin N
authors.initials: MN
authors.lastname: Sillence
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Lynch
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000420:Albuterol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004983:Ethanolamines / Q000008:administration & dosage / Q000494:pharmacology*; D000068759:Formoterol Fumarate; D006321:Heart / Q000187:drug effects*; D008297:Male; D018656:Muscle Fibers, Fast-Twitch / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018657:Muscle Fibers, Slow-Twitch / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D000068299:Salmeterol Xinafoate
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D004983:Ethanolamines; D018343:Receptors, Adrenergic, beta-2; D000068299:Salmeterol Xinafoate; D000420:Albuterol; D000068759:Formoterol Fumarate