Abstract
BackgroundBeta-adrenergic receptor agonists (BA) induce skeletal muscle hypertrophy, yet specific mechanisms that lead to this effect are not well understood. The objective of this research was to identify novel genes and physiological pathways that potentially facilitate BA induced skeletal muscle growth. The Affymetrix platform was utilized to identify gene expression changes in mouse skeletal muscle 24 hours and 10 days after administration of the BA clenbuterol.ResultsAdministration of clenbuterol stimulated anabolic activity, as indicated by decreased blood urea nitrogen (BUN; P < 0.01) and increased body weight gain (P < 0.05) 24 hours or 10 days, respectively, after initiation of clenbuterol treatment. A total of 22,605 probesets were evaluated with 52 probesets defined as differentially expressed based on a false discovery rate of 10%. Differential mRNA abundance of four of these genes was validated in an independent experiment by quantitative PCR. Functional characterization of differentially expressed genes revealed several categories that participate in biological processes important to skeletal muscle growth, including regulators of transcription and translation, mediators of cell-signalling pathways, and genes involved in polyamine metabolism.ConclusionGlobal evaluation of gene expression after administration of clenbuterol identified changes in gene expression and overrepresented functional categories of genes that may regulate BA-induced muscle hypertrophy. Changes in mRNA abundance of multiple genes associated with myogenic differentiation may indicate an important effect of BA on proliferation, differentiation, and/or recruitment of satellite cells into muscle fibers to promote muscle hypertrophy. Increased mRNA abundance of genes involved in the initiation of translation suggests that increased levels of protein synthesis often associated with BA administration may result from a general up-regulation of translational initiators. Additionally, numerous other genes and physiological pathways were identified that will be important targets for further investigations of the hypertrophic effect of BA on skeletal muscle.
Highlights
Beta-adrenergic receptor agonists (BA) induce skeletal muscle hypertrophy, yet specific mechanisms that lead to this effect are not well understood
Body weight gain tended to differ among the three groups of mice (P = 0.06), with a significant increase in body weight gain observed following 10 day clenbuterol treatment (10 D) clenbuterol administration compared to the C group (P < 0.05; Figure 2)
A total of 137, 56 and 4 probesets were differentially expressed based on false discovery rates (FDR) of 20, 10, and 5%, respectively, which correspond to P-values less than 0.0012, 0.00025, and 0.0000082, respectively
Summary
Beta-adrenergic receptor agonists (BA) induce skeletal muscle hypertrophy, yet specific mechanisms that lead to this effect are not well understood. Clenbuterol is known to induce a significant repartitioning effect by increasing the growth of skeletal muscle at the expense of fat tissues in most livestock species [3,5]. It is known that clenbuterol initiates these effects via activation of the β2-adrenergic receptor [3,5], the downstream mechanisms by which activation of these receptors results in increased muscle growth or decreased muscle atrophy are not clear. Endogenous proteinases including genes of the ubiquitin-proteasome pathway and calcium-dependent proteolytic enzymes have been reported to mediate protein turnover in skeletal muscle after administration of BA [14]. Changes in skeletal muscle expression of IGF1 and IGF2 mRNA have been observed shortly after the administration of clenbuterol to rodents [15], suggesting the regulation of these growth factors may be important in the initial response of skeletal muscle to BA
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