Myostatin negatively regulates cardiac muscle growth, development and performance

Jillian Patrice Interlichia

Myostatin is a known negative regulator of skeletal muscle growth and is suspected to similarly influence cardiac muscle. To test this hypothesis, we determined the effect of myostatin on the proliferation and differentiation of rat H9C2 cardiomyoblasts. Myostatin inhibited basal and insulin-like growth factor (IGF)-I stimulated proliferation in a dose dependent manner and partially blocked retinoic acid-induced differentiation. These cells expressed a full complement of myostatin receptors (Acvr2, Acvr2b, ALK4 & ALK5) and binding proteins (follistatin & follistatin-like protein (FSTL)-3), although some of the expression patterns differed considerably from those in skeletal muscle cells. To investigate myostatin's effect on cardiac function, echocardiography was performed on myostatin null and wild-type mice. Measurements of left ventricle internal diameter, but not wall thickness, were larger in null mice, which resulted in greater end diastolic and systolic volumes. Such differences are indicative of eccentric hypertrophy. Isoproterenol stress tests revealed a greatly enhanced response in null mice, whose hearts were also heavier. Fetal gene expression was similarly low in both wild-type and null mice further indicating that the eccentric hypertrophy was physiological and not pathological. Expression of follistatin and FSTL-3 were elevated in infarcted cardiac muscle of wild-type mice, although only follistatin levels were significantly different from non-infarcted muscle. These studies suggest that myostatin is a negative regulator of cardiac muscle growth and that the myostatin null mouse is a good model for investigating mechanisms of physiological hypertrophy. They further suggest that limiting myostatin action or bioavailability could improve cardiac muscle repair and performance. Additionally, myostatin control over insulin like growth factors (IGF) and IGF binding protein (IGFBP) levels was investigated. In neonatal mice, IGF-II, and IGF-IR were significantly elevated by approximately 70% and 250%, respectively, whereas in adult mice IGFIR was decreased by 40%. Changes in IGF/IGFBP production could presumably affect other tissues as well. Thus, we investigated the effect of myostatin knockout on body size over a period of seven months by measuring tibia epiphyseal plate width, tibia length, and tail length. However, there was no significant difference in these parameters between myostatin null and wild type mice at any time period.

Myostatin negatively regulates cardiac muscle growth, development and performance

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