Role of Masseter Muscle β2-Adrenergic Signaling in Regulation of Muscle Activity, Myosin Heavy Chain Transition, and Hypertrophy

Abstract

Abstract. Chronic administration of clenbuterol (CB), a lipophilic b 2 -adrenoceptor (b 2 -AR) agonist, induces skeletal muscle hypertrophy and slow-to-fast fiber-type transitions in mammalian species, but the mechanism and pathophysiological roles of these changes have not been explored. Here, we examined the effects of CB not only on masseter muscle mass, fiber diameter, and myosin heavy chain (MHC) composition, but also on daily muscle activity, a factor influencing muscle phenotype, by means of electromyogram analysis in rats. MHC transition towards faster isoforms was induced by 2-week CB treatment. In addition, daily duty time was increased at 1 day, 1 week, and 2 weeks after the start of CB treatment and its increase was greater at high activity level (6-fold) than at low activity level (2-fold). In order to examine whether these effects of CB were mediated through muscle or CNS b 2 -AR stimulation, we compared these effects of CB with those of salbutamol (SB), a hydrophilic b 2 -AR agonist. SB treatment induced masseter hypertrophy and MHC transition, like CB, but did not increase daily activity. These results suggest that CB-mediated slow-to-fast MHC transition with hypertrophy was induced through direct muscle b 2 -AR stimulation, but the increase of daily duty time was mediated through the CNS.

Role of phosphodiesterase 4 expression in the Epac1 signaling-dependent skeletal muscle hypertrophic action of clenbuterol

“…2) and previously by other groups (Wong et al 1997(Wong et al , 1998Zeman et al 2000), even though mice with a very high level of overexpression of b 2 -AR develop fibrosis (Liggett et al 2000). Since CB is known to promote lipolysis and decrease fat tissue, we speculate that those changes might compensate at least in part for the increase of the skeletal muscle mass, resulting in no significant difference of total BW between the Control and CB-treated groups (Miller et al 1988;McElligott et al 1989;Moore et al 1994;Abo et al 2012;Ohnuki et al 2013).…”

“…; Ohnuki et al. ). It is also reported that CB shows muscle selectivity and its anabolic effect seems greater in fast‐twitch muscle than in slow‐twitch skeletal muscle, though the mechanisms involved are unclear (Reeds et al.…”

“…The β ‐AR signaling pathway is considered a therapeutic target for the treatment of skeletal muscle wasting and weakness due to its critical role in the mechanisms controlling protein synthesis and degradation, in addition to the modulation of muscle fiber type (Ohnuki et al. , ; Umeki et al. , ).…”

“…Not surprisingly, numerous studies have focused on therapeutic applications of CB for ameliorating muscle wasting and for improving muscle function in disorders such as muscular dystrophy (Kissel et al 1998;Fowler et al 2004;Umeki et al 2015) and heart failure (Birks et al 2011). On the other hand, studies on animals have shown that CB impairs heart and skeletal muscle function, including tachycardia, cardiac hypertrophy, and decreased cardiac performance (Hoey et al 1995;Ohnuki et al 2013). It is also reported that CB shows muscle selectivity and its anabolic effect seems greater in fasttwitch muscle than in slow-twitch skeletal muscle, though the mechanisms involved are unclear (Reeds et al 1986;Ryall et al 2002;Sirvent et al 2014).…”

“…To determine MHC composition, the relative proportion of each MHC isoform was calculated as a percentage of total MHC content using the integrated dye density of the bands (Ohnuki et al. , ; Umeki et al. ).…”