Role of β-Adrenoceptor Signaling in Skeletal Muscle: Implications for Muscle Wasting and Disease

Abstract

The importance of beta-adrenergic signaling in the heart has been well documented, but it is only more recently that we have begun to understand the importance of this signaling pathway in skeletal muscle. There is considerable evidence regarding the stimulation of the beta-adrenergic system with beta-adrenoceptor agonists (beta-agonists). Although traditionally used for treating bronchospasm, it became apparent that some beta-agonists could increase skeletal muscle mass and decrease body fat. These so-called "repartitioning effects" proved desirable for the livestock industry trying to improve feed efficiency and meat quality. Studying beta-agonist effects on skeletal muscle has identified potential therapeutic applications for muscle wasting conditions such as sarcopenia, cancer cachexia, denervation, and neuromuscular diseases, aiming to attenuate (or potentially reverse) the muscle wasting and associated muscle weakness, and to enhance muscle growth and repair after injury. Some undesirable cardiovascular side effects of beta-agonists have so far limited their therapeutic potential. This review describes the physiological significance of beta-adrenergic signaling in skeletal muscle and examines the effects of beta-agonists on skeletal muscle structure and function. In addition, we examine the proposed beneficial effects of beta-agonist administration on skeletal muscle along with some of the less desirable cardiovascular effects. Understanding beta-adrenergic signaling in skeletal muscle is important for identifying new therapeutic targets and identifying novel approaches to attenuate the muscle wasting concomitant with many diseases.

Hypothalamic Sirt1 protects terminal Schwann cells and neuromuscular junctions from age‐related morphological changes

“…There are a few studies reporting on direct innervation of skeletal muscle fibers by nonmyelinated, noradrenergic fibers (Barker & Saito, 1981; Lynch & Ryall, 2008), suggesting that sympathetic actions on skeletal muscle are at least partially mediated by neural mechanisms. It has been reported that sympathetic neurons coinnervate several targets in muscle, including blood vessels, motor neurons, muscle fibers, and NMJs (Khan et al., 2016; Rudolf et al., 2013).…”

Effects of β2-agonists and exercise on β2-adrenergic receptor signaling in skeletal muscles

“…Numerous studies have shown that β2-agonists induce muscle hypertrophy in many species [10][11][12][13][14][15][16][17][18][19][20][21][22] . Experiments in mice lacking β1-AR, β2-AR, or both subtypes, have demonstrated that clenbuterol-induced effects, such as muscle hypertrophy, are mediated by β2-AR 10) .…”

“…Experiments in mice lacking β1-AR, β2-AR, or both subtypes, have demonstrated that clenbuterol-induced effects, such as muscle hypertrophy, are mediated by β2-AR 10) . β2-agonists promote muscle growth by stimulating protein synthesis and reducing protein degradation [11][12][13] . Furthermore, the hypertrophic response to β2-agonists is known to appear more frequently in fast-twitch muscles [11][12][13][14][15][16][17][18][19][20][21][22] .…”

“…β2-agonists promote muscle growth by stimulating protein synthesis and reducing protein degradation [11][12][13] . Furthermore, the hypertrophic response to β2-agonists is known to appear more frequently in fast-twitch muscles [11][12][13][14][15][16][17][18][19][20][21][22] . In addition to hypertrophic action, clenbuterol also induces the transformation of slow-twitch muscles to fast-twitch muscles [myosin heavy chain (MHC)I/β → MHCIIa → MHCIId/ x → MHCIIb] 14) .…”

“…2. Phosphorylated PKA regulates the activity of several proteins, including cAMP response element (CRE)-binding protein (CREB) 11,13) . However, single-dose clenbuterol treatment and acute exercise do not affect the level of CREB phosphorylation in skeletal muscles (Table 1) 22) , suggesting that the response of skeletal muscles to β2-agonists and exercise is not primarily dependent upon the activation of CREB.…”