Akt1-Mediated Skeletal Muscle Growth Attenuates Cardiac Dysfunction and Remodeling after Experimental Myocardial Infarction Araki et al: Muscle Growth Attenuates Cardiac Remodeling

Background It is appreciated that aerobic endurance exercise can attenuate unfavorable myocardial remodeling post myocardial infarction (MI). In contrast, little is known about the effects of increasing skeletal muscle mass, typically achieved through resistance training, on this process. Here, we utilized transgenic (TG) mice, that can induce the growth of functional skeletal muscle by switching Akt1 signaling on in muscle fibers, to assess the impact of glycolytic muscle growth on post-MI cardiac remodeling. Methods and Results Male non-induced TG mice and their non-transgenic littermates (control) were subjected to left anterior coronary artery ligation. Two days after surgery, mice were provided doxycycline in their drinking water to activate Akt1 transgene expression in a skeletal muscle-specific manner. Myogenic Akt1 activation led to diminished left ventricular dilation and reduced contractile dysfunction compared with control mice. Improved cardiac function in Akt1 TG mice was coupled to diminished myocyte hypertrophy, decreased interstitial fibrosis and increased capillary density. ELISA and protein array analyses demonstrated that serum levels of pro-angiogenic growth factors were upregulated in Akt1 TG mice compared with control mice. Cardiac eNOS was activated in Akt1 TG mice after MI. The protective effect of skeletal muscle Akt activation on cardiac remodeling and systolic function was abolished by treatment with the eNOS inhibitor L-NAME. Conclusions Akt1-mediated skeletal muscle growth attenuates cardiac remodeling after MI, and is associated with an increased capillary density in the heart. This improvement appears to be mediated by skeletal muscle to cardiac communication leading to activation of eNOS signaling in heart.