Take it to heart: myostatin inhibition, mighty mouse and the quest for a competitive edge.

Who does not want a sculpted, lean, toned, muscular, strong body? Who wants to suffer muscle wasting, severe weakness, limited mobility and the plethora of ailments associated with muscular dystrophy? Hardly anyone, for the quest for a competitive edge in health and the longing for a cure in disease may be as old as man's awareness of beauty and handicap. To keep strong, good-looking and illness-free (at least through a good part of our life), the human body is endowed with multiple mechanisms that promote cellular growth, repair damaged tissue and favour molecular turnover to renew life under placid or strenuous circumstances. Muscle growth is perhaps the most visible and complex of these mechanisms. In it, neurotrophic factors, hormones, transcriptional regulators, growth promoters, and countless cytosolic cofactors converge and interact with one another to increase the number (hyperplasia) and size (hypertrophia) of muscle cells. Enter myostatin, a member of the transforming growth factor (TGF)-β superfamily of secreted proteins which, by means of its dramatic negative influence on muscle growth and differentiation, appears to be the most devious spoilsport in the muscle-bulging party. Myostatin is a relatively novel player in the muscle signalling field, gaining a firm foot only after the discovery that knockout of the MSTN gene, which encodes myostatin, produces ‘mighty mice’ (McPherron et al. 1997), and that the rather monstrous-looking, ‘double-muscled’ Belgian Blue and Piedmontese cows have defective myostatin expression (Kambadur et al. 1997). After these observations, several studies have affirmed the role of myostatin as a chalone (endocrine secretion that inhibits physiological activity) in skeletal muscle: it is secreted by early-differentiating myoblasts, suppresses IGF-stimulated protein synthesis and directly inhibits muscle differentiation, proliferation and growth. Thus, the apparent beneficial effect on muscular mass and strength follow logically from inhibition of myostatin function. But what is the fate of other myostatin-secreting organs in these natural and experimenter-created models? In a recent issue of The Journal of Physiology, Rodgers et al. (2009) systematically explored the effect of myostatin ablation on murine cardiac differentiation, structure and function, and derived some of its most important functions in β-adrenergic responsiveness and in physiological versus pathological hypertrophy. The study is well justified, as myostatin mRNA was robustly detected in cardiac cells, but its function remained unclear. These authors used a homozygous myostatin knockout mouse model (MSTN−/−) with ∼30% increase in body weight (due mainly to skeletal muscle gain) and similar increase in cardiac mass. Thus, body weight/heart weight ratio of MSTN−/− mice was no different from wild-type littermates, but the authors cleverly used biochemical and echocardiographic data to determine that cardiac hypertrophy is not a compensatory mechanism to hypermuscularity. First, myostatin had a direct effect on isolated cells, as it inhibited IGF-stimulated and basal cardiomyoblast differentiation and proliferation, and second, the cardiac hypertrophy of MSTN−/− mice was eccentric, indicative of physiological hypertrophy, and not concentric, as typically results from isometric exercise and from conditions that increase after-load. In fact, physiological cardiac hypertrophy due to myostatin ablation was evidenced by normal levels of pathological genetic markers (ANP, BNP, α-actin and β-MHC), and by increased cardiac performance. Thus, selective myostatin inhibition may potentially aid in repairing damaged myocardium by inducing physiological hypertrophy, just as originally proposed for myostatin antibodies in the aid of the muscle wasting occurring in muscular dystrophy. What mechanisms explain myostatin's reduction of cardiac performance under basal and stress conditions?Rodgers et al. (2009) again elegantly measured critical parameters of excitation–contraction (e-c) coupling and concluded that intracellular Ca2+ transients and sarcoplasmic reticulum Ca2+ load were increased in MSTN−/− cardiomyocytes, but myofilament Ca2+ sensitivity was unaltered. Similarly, MSTN−/− cardiomyocytes displayed an augmented response to isoproterenol, a β-adrenergic agonist, increasing even further Ca2+ mobilization and contractility and enhancing multiple haemodynamic parameters. Overall, the cardiac effects characterized by Rodgers et al. (2009) affirm the notion that myostatin inhibition generates a ‘mighty mouse’ with no apparent deleterious effects, although caution should be exerted because no functional analysis of other organs was conducted, and long-term effects remain unclear. To date, there are no long-term studies of myostatin inhibition in humans, but Belgian Blue cows appear to have smaller hearts and a shorter lifespan, whereas whippet MSTN−/− dogs are actually slower than their leaner greyhound relatives. Where do the results of Rodgers et al. (2009) leave us? By clearly showing that myostatin knockdown enhances cardiac contractility, one could conceive performance-enhancing intervention based on myostatin inhibition, but outstanding questions remain. Specifically, how does myostatin fit in with other known control systems of cardiac function? How does its role relate, for example, to classical hypertrophic systems like calcineurin, CaMKII and Akt? Why would the body have a system in place to ‘brake’ cardiac hypetrophy and development? Could suppressing myostatin be bad for the heart, and under what circumstances? Clearly, the jury is still out for myostatin inhibition as the future in gene doping for desperate athletes.