Treatment with activin type ii receptor antibody improves cardiac function in mice after myocardial infarction

Abstract

Abstract Background Activin type ii receptor (ActRII) binding to its natural ligands including myostatin, activin, and growth development factor 11 negatively regulates muscle growth. Blockade of the ligands/ActRII signaling with human ActRII monoclonal antibody has been shown to increase body lean mass and reduce fat mass in patients with type 2 diabetes. However, the blockade effect on the ligands/ActRII signaling in heart failure with or without cardiac cachexia remains controversial. We hypothesized that the blockade effect on the ligands/ActRII signaling with a murine ActRII monoclonal antibody would improve cardiac function in a mouse model of heart failure. Methods Under anesthesia with isoflurane in oxygen, C57BL/6 mice were subjected to sham surgery or myocardial infarction (MI) by ligation of left anterior descending coronary artery to induce heart failure. Mice were randomized into treatment groups based on ejection fraction measured by Vevo 3100 Imaging System two weeks after MI. MI mice were treated weekly with vehicle (n=11), 10 mg/kg (n=12), or 20 mg/kg (n=12) ActRII antibody by subcutaneous injection for 8 weeks. Cardiac function was determined by Vevo 3100 Imaging system at 4, 8 weeks post-treatment, respectively. Body lean and fat mass were determined by Bruker's Whole Body Composition Analyzer. Myocardial infarct size was determined by Masson's trichrome staining on heart sections. Results Myocardial infarction markedly impaired cardiac function in mice. Ejection fraction reduced to 21.3±1.9% in MI mice compared to 56.3±1.2% in sham-operated mice (p<0.0001). Weekly treatment with 10 mg/kg or 20 mg/kg antibody significantly improved ejection fraction to 32.1±2.8%, and 35.9±2.9%, respectively (p<0.01 and p<0.001). Antibody treatment in MI mice also reduced MI-induced lung congestion by 5% and 8% (p<0.01), respectively. However, heart weight and myocardial infarct size in antibody treated mice were comparable to those in vehicle-treated mice. Moreover, antibody treatment dose-dependently increased body weight, which is further confirmed by increases in muscle mass and body lean mass measured by gravimetric analysis and body composition analyzer. Conclusion ActRII antibody dose-dependently improved cardiac function independent of myocardial infarct size post-MI. Although antibody significantly increased body weight and lean mass, it did not significantly increase heart weight, indicating that antibody treatment did not cause adverse remodeling post-MI while it remarkably improved cardiac function. Our data suggest that ActRII antibody could be a novel treatment for heart failure with reduced ejection fraction and may be particularly beneficial in patients with cachexia. Funding Acknowledgement Type of funding sources: None.