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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on July 14, 2006; DOI: 10.1124/jpet.106.107045

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Received for publication April 28, 2006.
Revised July 13, 2006.
Accepted for publication July 13, 2006.

Chronic treatment with the {beta}2-adrenoceptor agonist pro-drug BRL-47672 impairs rat skeletal muscle function by inducing a comprehensive shift to a faster muscle phenotype

David J. Baker 1*, D. Constantin-Teodosiu 1, Simon W. Jones 1, James A. Timmons 2, Paul L. Greenhaff 1

1 University of Nottingham 2 Karolinska Institutet

* Address correspondence to: E-mail: dbaker{at}kin.ucalgary.ca

Abstract

Discovering approaches to maintain or improve muscle function (fatigue resistance) in patients with cachexia, post-operative weakness and sarcopenia is of clinical importance. {beta}2-agonist treatment increases muscle mass yet alters fiber proportions, such that the net consequences on muscle function remains unclear. In the present study we focus on the contractile and metabolic consequences of chronic treatment with the {beta}2-agonist pro-drug BRL-47672 (BRL). Gastrocnemius-Plantaris-Soleus (GPS) muscles were harvested at rest and studied for fatigue characteristics during 4s and 20s of isometric stimulation (30 Hz, 10V, 200 ms) using the perfused hindlimb model. BRL treatment increased GPS mass by 21% (P< 0.05) while greater fatigue occurred during 20s of contraction (45% less work, P<0.05). Phenotypically, BRL resulted in 17% more Type IIb MyHC protein expression (P<0.001) and greater adenine nucleotide catabolism during 20s of contraction (P< 0.05). Chronic BRL treatment impaired maximal lipid oxidation capacity by 30% (P<0.05) and reduced GDH 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.


Key words: Adenine nucleotides, Beta-2 agonists, Fiber type, Muscle fatigue, Muscle wasting, Pro-drug


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