The potential and the pitfalls of β-adrenoceptor agonists for the management of skeletal muscle wasting

https://doi.org/10.1016/j.pharmthera.2008.06.003Get rights and content

Abstract

The β-adrenergic signaling pathway represents a novel therapeutic target for skeletal muscle wasting and weakness due to its role in the mechanisms controlling protein synthesis and degradation and in modulating fiber type. Stimulation of the pathway with β-adrenoceptor agonists (β-agonists) has therapeutic potential for muscle wasting disorders including: sarcopenia, cancer cachexia, disuse and inactivity, unloading or microgravity, sepsis and other metabolic disorders, denervation, burns, HIV-AIDS, chronic kidney or heart failure, and neuromuscular diseases. However, there are also pitfalls associated with β-agonist administration and clinical applications have so far been limited, largely because of cardiovascular side effects. In rats and mice, newer generation β-agonists (such as formoterol) can elicit an anabolic response in skeletal muscle even at very low doses, with reduced effects on the heart and cardiovascular system compared with older generation β-agonists (such as fenoterol and clenbuterol). However, the potentially deleterious cardiovascular side effects of β-agonists have not been obviated completely and so it is important to refine their development and therapeutic approach in order to overcome these obstacles. This review describes the therapeutic potential of stimulating the β-adrenergic signaling pathway with β-agonists, highlighting the beneficial effects on skeletal muscle structure and function and identifying some of the pitfalls associated with short- and long-term β-agonist administration. The review also identifies some important, but as yet unanswered questions, regarding the importance of β-adrenoceptor signaling in muscle health and disease and the strategies needed to improve the efficacy and safety of β-agonists for muscle wasting disorders.

Introduction

While the primary therapeutic use of β-adrenoceptor agonists (β-agonists) is for bronchodilation in the treatment of asthma, it became apparent that when administered at doses higher than those used therapeutically, these agents could elicit significant skeletal muscle growth. It is this property of β-agonists that has resulted in more than 25 years of research focused on their potential to prevent or reverse the muscle wasting and weakness associated with numerous conditions and pathologies, including sarcopenia (age-related muscle wasting), cancer cachexia, sepsis (and other forms of metabolic stress), denervation, disuse, burns, human immunodeficiency virus (HIV)-acquired immunodeficiency syndrome, chronic kidney or heart failure, chronic obstructive pulmonary disease, muscular dystrophies, and muscular dystrophies and other neuromuscular disorders.

Synthetic β-agonists such as cimaterol, clenbuterol, fenoterol, formoterol, salbutamol and salmeterol, are based on the chemical structure of adrenaline, and promote muscle growth via stimulation of β-adrenoceptors and subsequent activation of downstream signaling pathways. We have recently reviewed the role of β-adrenoceptor signaling in skeletal muscle with implications for health and disease (Lynch & Ryall, 2008). The purpose of this review is not to merely repeat this information, but to focus on the potential (and the pitfalls) of β-agonist therapies for conditions where muscle wasting and weakness are indicated, rather than on β-adrenoceptor signaling per se.

Skeletal muscle contains all three β-adrenoceptor subtypes (β1-, β2- and β3-adrenoceptors), with an ~ 10 fold greater proportion of the β2-adrenoceptor isoform than either β1- or β3-adrenoceptors (Williams et al., 1984, Kim et al., 1991). Although the β2-adrenoceptors are believed to be solely responsible for the β2-agonist-induced skeletal muscle hypertrophy (Hinkle et al., 2002), it is unclear whether β2-adrenoceptors are also responsible for changes to metabolic properties of the muscle. Furthermore, many of the β2-agonists employed in the past have actions on both β1- and β3-adrenoceptors. Therefore, for the remainder of this review, we will refer to the use of β-agonists, rather than discussing specifically the effects of β2-agonists.

Section snippets

Potential of β-agonist therapy

The hypertrophic response of skeletal (and cardiac) muscle following chronic, high-dose β-agonist administration has been associated with an increase in protein synthesis, a decrease in protein degradation, or a combination of both mechanisms (Lynch & Ryall, 2008). However, results remain equivocal as to the mechanism which predominantly mediates β-agonist-induced growth of skeletal muscle.

Canonical β-agonist signaling has been well described and involves selective coupling to a heterotrimeric

Pitfalls of β-agonist therapy

While the β-adrenergic signaling pathway represents a novel therapeutic target for age-related muscle wasting and weakness due to its involvement in pathways that modulate skeletal muscle growth and fiber type, it must be recognized that this pathway is highly susceptible to downregulation with chronic stimulation, and this may have detrimental effects once exogenous stimulation is stopped. Also of concern is the presence of β-adrenoceptors in tissues other than skeletal muscle. Thus, any

Future directions for therapeutic approaches utilizing β-agonists

As described in Section 3, some of the most serious consequences associated with chronic β-agonist administration relate to the systemic responses to β-adrenoceptor activation. Much research is currently focused on developing new methods of drug administration that limit unwanted systemic effects, with many having the potential to improve the safe delivery of β-agonists to skeletal muscle.

Many muscle wasting conditions, such as that associated with the normal process of aging, require only

Summary and conclusions

The β-adrenergic signaling pathway represents a novel therapeutic target for the treatment of skeletal muscle wasting and weakness due to its critical roles in the mechanisms controlling protein synthesis and degradation and the modulation of muscle fiber type (Lynch & Ryall, 2008). Although stimulation of the β-adrenergic signaling pathway with β-agonists has great therapeutic potential for muscle wasting disorders, there are some obvious pitfalls with this approach and clinical applications

Acknowledgments

The funding for this research has been provided by generous grants from the Australian Research Council Discovery-Project funding scheme (DP0665071, DP0772781), the National Health and Medical Research Council of Australia (350439, 454561, 509313), the Muscular Dystrophy Association (USA, 3595, 4167), Pfizer Inc. (USA), and Merck & Co. Inc. (USA).

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