Absence of Myostatin Improves Cardiac Function After Myocardial Infarction

Abstract

Myostatin is a well-established inhibitor of skeletal muscle development. However, the role of myostatin in cardiac muscle, specifically in acute myocardial infarction (MI), is less clear. Therefore, the aim of this thesis is to determine the potential effects of myostatin following an acute MI. Methods: The first study examined the concentration of myostatin mRNA at different time points following an induction of MI in an ovine model. Using a murine model with a constitutive deletion of the myostatin gene (Mstn-/-) and compared with WT controls, the second study investigated several clinical outcomes in the absence of myostatin at 28 days following an acute MI via ligation of the left anterior descending (LAD) artery. At 28 days post-MI, mice were injected with BrdU, then euthanized and their hearts were excised and weighed, followed by histological examination, immunohistochemistry and indirect immunofluorescence. Findings: When compared with non-infarcted ovine controls, the concentration of myostatin mRNA was reduced and reached a nadir at day one post-MI in the peri-infarct region of the myocardium before a progressive restoration of the concentration of myostatin mRNA to that of the controls (P < 0.01). This dynamic change was not observed in the distant region of the myocardium post-MI (P < 0.01). In the Mstn-/- mice, the total body weight was larger than WT mice (39.21 ± 0.57g vs 24.66 ± 0.37g, P < 0.001) and remained so during the study period. The mortality rate in Mstn-/- mice was lower compared with WT mice post-surgery (0% vs 20%, P < 0.05). Ligation of the LAD artery resulted in a similar infarct size in both the Mstn-/- and WT mice (9.9 ± 1.9% vs 12.5 ± 1.7%, P = 0.38). Cardiac ejection fraction (EF) as determined by echocardiography was similar at baseline between the genotypes (61.5 ± 1.2% vs 60.6 ± 1.3%, P = 0.15) and following induction of MI, a similar degree of reduction in EF resulted (-8.6 ± 2.2% vs -7.3 ± 2.7%, P = 0.6). However, at 28 days post-MI, EF was restored to baseline in Mstn-/- but not in the WT mice (61.8 ± 1.1% vs 57.1 ± 2.3%, P < 0.01). Mstn-/- mice had a lower mean increased in heart rate post-surgery compared with WT mice (+23.6 ± 13.7bpm vs +109.5 ± 14.3bpm, P < 0.01). Induction of MI resulted in a lower increased in mean arterial pressure in Mstn-/- mice compared with WT mice (-7 ± 3.9mmHg vs +4.4 ± 3.9mmHg, P < 0.05). There was no difference in the number of BrdU positive cells, the percent of apoptotic cardiomyocytes, and the size of cardiomyocytes between Mstn-/- and WT mice. However, a reduction in the extent of collagen deposition was observed in the Mstn-/- mice compared with WT mice (41.9 ± 2.8% vs 54.7 ± 3.4%, P < 0.05). Conclusion: The absence of myostatin protects the function of the heart following an acute MI likely via inhibiting the extent of fibrosis. Further studies are needed to determine whether administration of myostatin antagonists could be used as an effective adjunct to the current management of acute MI.