title: Chronic treatment with the beta(2)-adrenoceptor agonist prodrug BRL-47672 impairs rat skeletal muscle function by inducing a comprehensive shift to a faster muscle phenotype.
abstract: Discovering approaches to maintain or improve muscle function (fatigue resistance) in patients with cachexia, postoperative weakness, and sarcopenia is of clinical importance. beta(2)-Agonist treatment increases muscle mass, yet it alters fiber proportions such that the net consequences on muscle function remain unclear. In the present study, we focus on the contractile and metabolic consequences of chronic treatment with the beta(2)-agonist prodrug BRL-47672 (BRL). Gastrocnemius-plantaris-soleus (GPS) muscles were harvested at rest and studied for fatigue characteristics during 4 and 20 s of isometric stimulation (30 Hz; 10 V; 200 ms) using the perfused hind limb model. BRL treatment increased GPS mass by 21% (P < 0.05), whereas greater fatigue occurred during 20 s of contraction (45% less work; P < 0.05). Phenotypically, BRL resulted in 17% more type IIb myosin heavy chain protein expression (P < 0.001) and greater adenine nucleotide catabolism during 20 s of contraction (P < 0.05). Chronic BRL treatment impaired maximal lipid oxidation capacity by 30% (P < 0.05) and reduced glutamate dehydrogenase activity by 15% (P < 0.05). We conclude that beta(2)-agonist induced muscle hypertrophy may be clinically limited as impaired energy metabolism and function occur, presumably as a consequence of the shift in muscle phenotype.
authors.affiliation: Centre for Integrated Systems Biology and Medicine, School of Biomedical Science, University of Nottingham, Nottingham, United Kingdom. dbaker@kin.ucalgary.ca
authors.forename: David J
authors.initials: DJ
authors.lastname: Baker
authors.forename: D
authors.initials: D
authors.lastname: Constantin-Teodosiu
authors.forename: Simon W
authors.initials: SW
authors.lastname: Jones
authors.forename: James A
authors.initials: JA
authors.lastname: Timmons
authors.forename: Paul L
authors.initials: PL
authors.lastname: Greenhaff
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D006003:Glycogen / Q000032:analysis; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000502:physiology; D018995:Myosin Heavy Chains / Q000032:analysis; D009930:Organic Chemicals / Q000494:pharmacology; D010641:Phenotype; D051381:Rats; D017208:Rats, Wistar
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; C089126:BRL 47672; D009930:Organic Chemicals; D000255:Adenosine Triphosphate; D006003:Glycogen; D018995:Myosin Heavy Chains