The potential and the pitfalls of β-adrenoceptor agonists for the management of skeletal muscle wasting
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).
References (196)
- et al.
Effect of the β2-adrenergic agonist clenbuterol on the growth of fast- and slow-twitch skeletal muscle of the dystrophic (C57BL6J dy2J/dy2J) mouse
Comp Biochem Physiol C Pharmacol Toxicol Endocrinol
(1995) Formoterol: pharmacology, molecular basis of agonism, and mechanism of long duration of a highly potent and selective β2-adrenoceptor agonist bronchodilator
Life Sci
(1993)- et al.
Apoptosis signalling is essential and precedes protein degradation in wasting skeletal muscle during catabolic conditions
Int J Biochem Cell Biol
(2008) - et al.
Three fast myosin heavy chains in adult rat skeletal muscle
FEBS Lett
(1988) - et al.
Evidence-based pharmacologic management of pulmonary arterial hypertension
Clin Ther
(2007) - et al.
Decreased myofibrillar protein breakdown following treatment with clenbuterol
J Surg Res
(1991) - et al.
Comparative effects of β2-adrenergic agonists on muscle waste associated with tumour growth
Cancer Lett
(1997) - et al.
Effects of clenbuterol on skeletal muscle mass, body composition, and recovery from surgical stress in senescent rats
Metabolism
(1991) - et al.
The E3 Ligase MuRF1 degrades myosin heavy chain protein in dexamethasone-treated skeletal muscle
Cell Metab
(2007) - et al.
Ca2+-dependent proteolysis in muscle wasting
Int J Biochem Cell Biol
(2005)
Essential role for G protein-coupled receptor endocytosis in the activation of mitogen-activated protein kinase
J Biol Chem
Interaction of left ventricular relaxation and filling during early diastole in human subjects
Am J Cardiol
Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1a muscle-specific knock-out animals
J Biol Chem
Low dose formoterol administration improves muscle function in dystrophic mdx mice without increasing fatigue
Neuromuscul Disord
Clenbuterol increases lean muscle mass but not endurance in patients with chronic heart failure
J Heart Lung Transplant
Characterization of β1- and β2-adrenoceptors in rat skeletal muscles
Biochem Pharmacol
Adverse effects of beta-agonists: are they clinically relevant?
Am J Respir Med
Beneficial effects of chronic pharmacological manipulation of β-adrenoreceptor subtype signaling in rodent dilated ischemic cardiomyopathy
Circulation
Cardioprotective and survival benefits of long-term combined therapy with β2 AR agonist and β1 AR blocker in dilated cardiomyopathy post-myocardial infarction
J Pharmacol Exp Ther
Pharmacological stimulation of β2-adrenergic receptors (β2AR) enhances therapeutic effectiveness of β1AR blockade in rodent dilated ischemic cardiomyopathy
Heart Fail Rev
Transforming growth factor βs are upregulated in the rat masseter muscle hypertrophied by clenbuterol, a β2 adrenergic agonist
Br J Pharmacol
Phosphodiesterase inhibition promotes the transition from compensated hypertrophy to cardiac dilatation in rats
Pflugers Arch
The ubiquitin–proteasome system and skeletal muscle wasting
Essays Biochem
The risk of myocardial infarction associated with inhaled β-adrenoceptor agonists
Am J Resp Crit Care Med
Chronic treatment with the β2-adrenoceptor agonist prodrug BRL-47672 impairs rat skeletal muscle function by inducing a comprehensive shift to a faster muscle phenotype
J Pharmacol Exp Ther
Hormonal and metabolic responses to the stress of transport and slaughterhouse procedures in clenbuterol-fed pigs
J Vet Med
Exercise capacity and cardiac function of rats with drug-induced cardiac enlargement
J Appl Physiol
The mAKAP signalosome and cardiac myocyte hypertrophy
IUBMB Life
Pentoxifylline inhibits Ca2+-dependent and ATP proteasome-dependent proteolysis in skeletal muscle from acutely diabetic rats
Am J Physiol Endocrinol Metab
β2-Adrenoceptor agonist fenoterol enhances functional repair of regenerating rat skeletal muscle after injury
J Appl Physiol
β-Adrenoceptor signaling in regenerating skeletal muscle after β-agonist administration
Am J Physiol Endocrinol Metab
Isoproterenol-induced myocardial fibrosis in relation to myocyte necrosis
Circ Res
Calcium ion in skeletal muscle: its crucial role for muscle function, plasticity, and disease
Physiol Rev
SIK1 is a class II HDAC kinase that promotes survival of skeletal myocytes
Nat Med
Cardiac excitation–contraction coupling
Nature
Hemodynamics during the acute phase of myocardial damage caused by isoproterenol
Can J Biochem Physiol
Cyclic nucleotide phosphodiesterase isozymes expressed in mouse skeletal muscle
Can J Physiol Pharmacol
Fiber type populations and Ca2+-activation properties of single fibers in soleus muscles from SHR and WKY rats
Am J Physiol
Pentoxifylline decreases body weight loss and muscle protein wasting characteristics of sepsis
Am J Physiol
Clenbuterol treatment affects myosin heavy chain isoforms and MyoD content similarly in intact and regenerated soleus muscles
Acta Physiol Scand
The formation of skeletal muscle: from somite to limb
J Anat
Adverse effects of beta2-agonists
Molecular pharmacotherapeutic targeting of PDE5 for preservation of penile health
J Androl
Anticachectic effects of formoterol: a drug for potential treatment of muscle wasting
Cancer Res
Doping and respiratory system
Monaldi Arch Chest Dis
Cellular and molecular regulation of muscle regeneration
Physiol Rev
Anabolic effects of clenbuterol on skeletal muscle are mediated by β2-adrenoceptor activation
Am J Physiol
Opposing effects of β1- and β2-adrenergic receptors on cardiac myocyte apoptosis: role of a pertussis toxin-sensitive G protein
Circulation
Muscle protein waste in tumor-bearing rats is effectively antagonized by a β2-adrenergic agonist (clenbuterol). Role of the ATP-ubiquitin-dependent proteolytic pathway
J Clin Invest
Switching of the coupling of the β2-adrenergic receptor to different G proteins by protein kinase A
Nature
Cited by (78)
Use of transcriptome sequencing to explore the effect of CSRP3 on chicken myoblasts
2023, Journal of Integrative AgricultureAging-related modifications to G protein-coupled receptor signaling diversity
2021, Pharmacology and TherapeuticsCitation Excerpt :This indicates that the upregulation of β-arrestins in the patients may contribute to the resistance to the therapeutic effects of levodopa often observed (Bychkov et al., 2008). In normal healthy physiological conditions, a crosstalk exists between the insulin/insulin-like growth factor 1 receptors and GPCR-based signaling pathways entrained by both G proteins and β-arrestins (Blair & Marshall, 1997; Lin, Daaka, & Lefkowitz, 1998; Povsic et al., 2003; Roudabush, Pierce, Maudsley, Khan, & Luttrell, 2000; Ryall & Lynch, 2008). For example, a decrease in β-arrestin2 expression is evident in well-characterized models of T2DM.
The emerging role of the sympathetic nervous system in skeletal muscle motor innervation and sarcopenia
2021, Ageing Research ReviewsVAMS and StAGE as innovative tools for the enantioselective determination of clenbuterol in urine by LC-MS/MS
2021, Journal of Pharmaceutical and Biomedical AnalysisFlavan 3-ol delays the progression of disuse atrophy induced by hindlimb suspension in mice
2017, Experimental Gerontology