Myostatin: an overlooked player in heart failure

Myostatin controls skeletal muscle development by inhibiting muscle fibre growth and myoblast proliferation and differentiation. Because of the profound effects of myostatin on skeletal muscle development, its potential function in other tissues has attracted much less attention. Nevertheless, an increasing number of papers have addressed potential cardiac functions and in the past year two papers have appeared in this journal showing a complex regulation of myostatin levels in heart failure, both in animals and in men. Myostatin is a secreted protein belonging to the TGF-b superfamily. It is predominantly expressed in skeletal myocytes, but has also been detected in heart and in adipose tissue, although at lower levels. Myostatin is produced as an inactive protein consisting of an N-terminal pre-propeptide region and a highly conserved C-terminal active domain. After proteolytic processing the mature C-terminal form is secreted as a latent form in complex with the latency associated peptide (LAP, the propeptide). Only when this mature dimeric C-terminus is released from the LAP can it bind to the activin receptor, ActRIIB, and activate the intracellular Smad signal transduction pathway, thereby negatively regulating muscle development. In 1997, the myostatin knock out mouse was generated and showed strongly increased muscle development, twice to three times the normal muscle size (Figure 1A). In this ‘mighty mouse’, increased muscle size was a result of both increased proliferation (hyperplasia) and cellular growth (hypertrophy). Interestingly, subsequent genetic analysis of so called ‘double muscle’ cattle revealed mutations in the myostatin gene that compromised functionality, resulting in increased muscle growth. The massive muscle development in the myostatin mutated Belgian Blue bovine is a wellknown example and primarily a result of hyperplasia in this animal. The inhibitory role of myostatin in muscle development was further supported by overexpression of myostatin in mice, which caused cachexia. On the basis of these results myostatin targeting has been suggested as a potential therapeutic option to treat muscle wasting diseases, like cachexia and muscular dystrophy. In contrast to the profound effect of myostatin on skeletal muscle development, the effects on the heart appear to be much more subtle. Reports on heart weight in myostatin knockout mice have shown either no difference compared with the wildtype, –11 an increase or an increase which paralleled the overall body mass increase. Heart function appeared to be somewhat improved in knockout mice and this difference became more prominent with increasing age. Transgenic overexpression of myostatin in heart and muscle reduced heart weight in males, but did not affect heart function. Together, these data indicate that under normal conditions myostatin plays only a minor role in heart development and function. These experiments did not, however, exclude the possibility that this protein could play a more prominent role under certain pathophysiological conditions. Recently, it was shown that in a rat model of post-MI heart failure, myostatin mRNA and protein levels were increased in the heart. This confirmed and extended earlier observations of a heart failure study in which rats with aortacaval shunts (volume overload) showed increased myostatin protein and mRNA levels. Therefore, different forms of heart failure appear to induce myostatin expression in the rat heart. Also, in vitro, it had been shown that treatment of rat neonatal cardiomyocytes with Angiotensin II, a hypertrophic stimulus, resulted in increased myostatin gene and protein expression and formation of more active myostatin. Similar results were obtained with mechanical stretch, indicating that both hormonal and mechanical hypertrophic stimuli trigger myostatin expression and activation in rat cardiomyocytes. Importantly, myostatin overexpression was able to inhibit hypertrophy (alpha-adrenergic, phenylephrine) induced growth of cardiomyocytes in vitro, indicating that in cardiomyocytes myostatin can also act as a growth inhibitor. In this issue of the European Journal of Heart Failure it is now shown that myostatin levels are also changed in heart biopsies of severe heart failure patients. Although, the full length protein levels were not increased in these patients, the levels of processed pro-peptide were higher and the authors argue that this is indicative of enhanced myostatin processing, ultimately resulting in more active myostatin in the heart. Even though the authors did not