Muscle Plasticity and β₂‐Adrenergic Receptors: Adaptive Responses of β₂‐Adrenergic Receptor Expression to Muscle Hypertrophy and Atrophy

Abstract

We discuss the functional roles of β2-adrenergic receptors in skeletal muscle hypertrophy and atrophy as well as the adaptive responses of β2-adrenergic receptor expression to anabolic and catabolic conditions. β2-Adrenergic receptor stimulation using anabolic drugs increases muscle mass by promoting muscle protein synthesis and/or attenuating protein degradation. These effects are prevented by the downregulation of the receptor. Endurance training improves oxidative performance partly by increasing β2-adrenergic receptor density in exercise-recruited slow-twitch muscles. However, excessive stimulation of β2-adrenergic receptors negates their beneficial effects. Although the preventive effects of β2-adrenergic receptor stimulation on atrophy induced by muscle disuse and catabolic hormones or drugs are observed, these catabolic conditions decrease β2-adrenergic receptor expression in slow-twitch muscles. These findings present evidence against the use of β2-adrenergic agonists in therapy for muscle wasting and weakness. Thus, β2-adrenergic receptors in the skeletal muscles play an important physiological role in the regulation of protein and energy balance.

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.…”

“…2). In one such pathway, the receptor-coupled Gαi dissociates from the heterodimeric Gβγ complex, and free Gβγ subunits then activate the MAPK signaling pathway 11,13,30) .…”