To our knowledge, this is the first study investigating myostatin regulation in the pediatric heart, and our primary findings in this small cohort of patients are (i) myostatin expression is increased in compensated LV HF (LV-OHT) compared to paired normal RV control (RV-OHT) and unpaired normal RV control (RVOT), (ii) myostatin expression is increased in decompensated biventricular HF after mechanical unloading (BiVAD) compared to both compensated HF (OHT) and control (RVOT), (iii) the myostatin/IGF-1 ratio increases in correlation with the degree of ventricular dysfunction, and (iv) MEF-2 expression is increased in compensated LV HF (LV-OHT) vs. normal LV (Adult Normal) and further increased in decompensated biventricular failure after mechanical unloading (BiVAD).
The role of myostatin in HF has not yet been definitively determined 
. Accumulating evidence suggests that myostatin may be a critical regulator of cardiac remodeling. In animals, it has been observed that myostatin is upregulated following infarct in sheep and rats 
, volume overload in rats 
, and pressure overload in mice 
. In addition, inhibition of myostatin in the mdx
model of DMD accelerates the onset of systolic dysfunction and LV chamber dilatation 
. In humans, myostatin has been reported to be increased in the serum 
, heart 
, and skeletal muscle 
of adult HF patients, although one study did report decreased serum myostatin in HF patients 
. In addition, we have previously reported that myostatin activation is increased in adult HF of both ischemic and non-ischemic etiologies 
, and now we have determined that myostatin expression is increased in HF secondary to CHD. Additional studies will need to be performed in which myostatin is both inhibited and overexpressed in an animal model to determine its exact role in HF as well as the therapeutic potential of manipulation of myostatin expression in this setting.
It is interesting to note the much larger relative increase in myostatin after BiVAD support versus LVAD support 
. The loss of feedback inhibition after mechanical unloading appears more pronounced with biventricular failure–whether different inhibitory pathways are activated/de-activated or other stress pathways are involved remains under investigation. This increase in myostatin following mechanical unloading may have been expected given the fact that exercise training (i.e. loading) results in decreased skeletal muscle myostatin in healthy humans and in several pathological states 
, including HF 
and insulin resistance 
, as well as in decreased skeletal and cardiac muscle myostatin expression in a rat model of HF 
. It is possible that myostatin may mediate cellular atrophy during periods of mechanical unloading and that myostatin levels must decrease to allow physiological hypertrophy during exercise training. Additonal experiments in animal models will need to be performed to test these hypotheses.
We also examined the relationship between myostatin and IGF-1 in this study and found that the ratio of myostatin to IGF-1 increased as ventricular function decreased. A link between myostatin and IGF-1 in the heart has been previously suggested 
. Shyu et al
found that myostatin is increased following cardiomyocyte stretch in culture and that this increase in expression is dependent upon IGF-1 secretion and subsequent signaling through the p38 pathway 
. Based on these data, a model has been proposed whereby IGF-1 signals preferentially via Akt under physiologic conditions to promote physiologic hypertrophy and/or cell survival. There is also likely baseline signaling through p38, which leads to increased myostatin expression via the MEF-2 transcription factor, thus exerting negative feedback on the Akt growth pathway via PTEN 
. However, under pathologic conditions such as pressure and/or volume overload in the failing heart, an unknown trigger may occur, which causes IGF-1 to signal predominantly through the p38/MEF-2 pathway and which results in increased expression of myostatin out of proportion to IGF-1. The stimulus for this trigger may be pathologic stretch in HF, as suggested by Shyu et al 
. If this is the case, we believe that an increased myostatin to IGF-1 ratio may be a clinical marker of worsening HF. Indeed, we observed increased MEF-2 in conditions where we also observed increased myostatin, which supports the proposed pathway. Future effort will be directed towards examining p38 and Akt signaling in these patients.
It is unclear at this point whether the increased myostatin to IGF-1 ratio causes or contributes to ventricular dysfunction in HF. It is known that decreased activity of the growth hormone (GH)/IGF-1 axis (low IGF-1 syndrome) is predictive of poorer outcomes and higher mortality in HF 
, and that GH replacement, which increases IGF-1 expression, can lead to increased peak oxygen uptake and exercise duration as well as higher quality of life 
. This therapy may function by restoring the physiological myostatin/IGF-1 ratio and overcoming pathologic repression of IGF-1 by myostatin. Our findings represent a small sample cohort, and additional experiments in which expression of both myostatin and IGF-1 is manipulated will need to be performed in an animal model of HF to delineate the significance of the myostatin/IGF-1 ratio in HF further.
In summary, we have demonstrated for the first time that myostatin expression is increased in pediatric compensated LV failure and further increases in decompensated biventricular failure after mechanical support. In addition, we observed that the myostatin/IGF-1 ratio may increase as ventricular function decreases. Future investigation is needed to determine the effects of myostatin inhibition and overexpression in HF.