Don't ‘agonise’ over the mechanisms underlying β-agonist-induced muscle hypertrophy!

Authors

  • P. J. Atherton,

    1. University of Nottingham, Division of Clinical Physiology, School of Graduate Entry Medicine and Health, Royal Derby Hospital, Uttoxeter Road, Derby DE22 3DT, UK
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  • N. J. Szewczyk

    1. University of Nottingham, Division of Clinical Physiology, School of Graduate Entry Medicine and Health, Royal Derby Hospital, Uttoxeter Road, Derby DE22 3DT, UK
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Email: philip.atherton@nottingham.ac.uk

The metabolic and physical characteristics of skeletal muscles demonstrate remarkable plasticity with perhaps the most striking example being changes in mass, for instance muscles hypertrophy in response to loading (e.g. resistance exercise) and atrophy in response to unloading (e.g. bed-rest). Moreover, pathological atrophy accompanies many other conditions, including cancer (cachexia), trauma, renal failure and heart failure. Muscle atrophy under these conditions may also be associated with mild-to-severe disuse but is exacerbated by cachectic signals independent of reduced neural input (e.g. inflammation; Rieu et al. 2009). To date efficacious treatment options for muscle atrophy are extremely limited.

Muscle atrophy occurs when muscle protein breakdown (MPB) chronically exceeds protein synthesis (MPS) and likewise, hypertrophy when MPS exceeds MPB. However, there are numerous scenarios through which this could occur such that atrophy could be caused e.g. when MPS↓ MPB↔or MPS↑, MPB↑↑. Moreover, it would be naive to assume that the time course of changes in protein turnover regulating atrophy are homogeneous such that it is perfectly reasonable to suppose e.g. at first MPS↓ MPB↔, but later MPS↓ MPB↑. Importantly, this supposition is likewise true for pharmacological interventions which may also exhibit distinct temporal (e.g. acute vs. chronic) effects on protein turnover. Therefore, if one is to solve the conundrum of how to treat atrophy, it is imperative to temporally define (a) the underlying changes in protein turnover regulating atrophy, and (b) how potential therapeutic interventions modulate protein turnover. Viz, there is no point using a drug that specifically suppresses MPB when MPB isn't increased!

In a recent issue of The Journal of Physiology, René Koopman and colleagues elegantly investigated the mechanisms by which a promising pharmaceutical agent called formoterol may help in the fight against muscle atrophy (Koopman et al. 2010). Formoterol belongs to the β-agonist drug category due to its actions on the β-adrenoreceptor (present in heart, smooth and skeletal muscles), which couples to a heterotrimeric GTP-binding protein (Gαβγ) to initiate intracellular signalling. Indeed, β-agonism has been long known to stimulate skeletal muscle growth so you may well ask why we are not already using β-agonists clinically. To date, their potential has been limited by the associated adverse effects, most notably cardiac hypertrophy e.g. with clenbuterol. However, newer generation β-agonist such as formoterol demonstrate a greater selectivity for skeletal muscle than heart and also induce skeletal muscle growth at lower doses – equivalent to those currently used for bronchodilation – making them a more viable therapeutic option (Ryall et al. 2006).

In the article, the Australia- and France-based workers administered daily injections of formoterol to growing mice. After treatment for 28 days, the authors reported skeletal muscle fibre hypertrophy and increased muscle-to-body weight ratios, thus proving the efficacy of formoterol as an anabolic agent. Moreover, by sampling muscle temporally (at days 1, 7 and 28) the authors were able to distinguish acute and chronic effects of formoterol, an approach which proved invaluable in deciphering its anabolic actions. For instance, after the first injection of formoterol the authors noted that despite there being no acute increase in MPS there was a specific decrease in the maximal activity of the Ca2+-dependent proteases (calpains), which persisted throughout the measured time course. Despite the limitation that the authors did not measure ‘bulk’ MPB using dynamic tracer methods (unlike for MPS), these findings may imply that Ca2+-mediated MPB is reduced by formoterol, and thus it could be used to counter atrophy where this pathway is hyperactive, such as in sepsis. In contrast, increased MPS and associated anabolic signals (e.g. ribosomal protein S6 kinase 1; S6K1) were evident chronically, after 7 days of formoterol treatment, perhaps providing therapeutic promise where MPS is reduced such as during immobilization. Therefore, in a nutshell it would seem that formoterol is not a ‘one trick pony’ as it possesses the capacity to increase MPS and decrease MPB (Fig. 1), thereby making it an attractive pharmaceutical to deal with many muscle wasting conditions.

Figure 1.

Temporal regulation of skeletal muscle hypertrophy by formoterol
Continuous lines: measured effects; dashed lines: possible effects

The present article by Koopman and colleagues has provided an excellent launch pad to our understanding of the complex anabolic functions of formoterol – but what should we do next? Evidently we need to refine initial work on newer generation β-agonists in terms of optimal dosage to increase skeletal muscle mass while preventing associated cardiovascular, and perhaps metabolic and functional capacities of β-agonist treated muscle (Baker et al. 2006). We should also aim to advance this work from growing mice to understand how β-agonists work in weight stable humans. Finally, the ultimate goal of translating the use of β-agonists to the clinic will depend upon our determining the temporal changes in protein turnover that underlie the large number of muscle wasting conditions in order to identify which are best suited to treatment with β-agonists.