| Myostatin is well established as a negative regulator of skeletal muscle growth, and it may play a role in controlling cardiomyocyte size as well. The goals of this study were (i) to analyze myostatin expression and activation in the failing human heart before and after implantation of a left ventricular assist device (LVAD), (ii) to characterize the regulation of myostatin expression following cardiac stress in vitro, and (iii) to examine the role of myostatin in the regulation of cardiomyocyte size by overexpressing and inhibiting myostatin both in vitro and in postnatal mice. Left ventricular tissue pairs were collected at LVAD implantation and at cardiac transplantation/LVAD explantation in patients with advanced ischemic (ICM) and non-ischemic (DCM) heart failure (HF). Serum was collected independently from patients with stable HF and from healthy controls. Neonatal cardiomyocytes from Wistar rats were cultured and stressed with phenylephrine. Adenovirus was used to overexpress myostatin or dominant negative myostatin in culture. Several adeno-associated virus (AAV) serotypes were screened to determine which displayed the greatest cardiac tropism. Once identified, AAV9 was used to overexpress myostatin or dominant negative myostatin in C57/B16 mice, and the effects on cardiac mass and function were analyzed. Myostatin activation is increased in patients with HF and further increases with LVAD support in DCM. Serum myostatin levels were significantly higher in HF patients versus normal. Myostatin expression is upregulated following stress in culture in an Erk-dependent and is associated with increased nuclear translocation and DNA binding activity of MEF-2. Myostatin overexpression leads to decreased and myostatin inhibition to increased cardiac growth both in vitro and in vivo due to modulation of Akt and NFAT3 pathways. This is the first clinical evidence that myostatin activation is increased in HF, where myostatin may negatively regulate cardiac hypertrophy and may mediate regression of cellular hypertrophy after mechanical unloading with LVAD support. In vitro and in this mouse model, myostatin negatively regulates cardiac growth, and further studies are needed to investigate the role of myostatin in the failing heart, especially in light of ongoing clinical trials aimed at increasing muscle mass in dystrophic patients via myostatin inhibition. |
