Aortic Banding and Low‐Intensity Exercise Training do not Alter Autophagy in a Yucatan Mini‐Swine Model of Pressure Overload‐Induced Heart Failure

Abstract

The autophagy‐lysosome system is an essential intracellular proteolytic process mediating recycling of dysfunctional proteins and organelles. This process is important to cellular renovation, and activation of autophagy by exercise training (ET) is considered essential to the maintenance of cellular vitality. However, the implications of chronic low‐intensity ET on autophagic function in an experimental setting of heart failure (HF) remains unclear. The purpose of this study was to determine if autophagy contributes to cardiovascular dysfunction that is treatable by ET in a pre‐clinical model of pressure overload‐induced HF. We hypothesized ET would prevent aortic banding‐induced decreases in autophagy in the heart, coronary vasculature, and skeletal muscle. Male Yucatan mini‐swine (29–32 kg; 8 mo‐old) were assigned to the following groups (6–7 pigs/groups): control (CON), heart failure (HF), heart failure low‐intensity continuous ET (HF‐CT), and heart failure low‐intensity interval ET (HF‐IT). Chronic pressure overload was induced by an aortic band placed on the ascending aorta proximal to the brachiocephalic artery. Two months post‐surgery and after the development of pathological hypertrophic remodeling, animals began treadmill ET 3 times/week at 55 minutes/session for 17 weeks. Autophagic markers measured by protein level of LC3B (a marker of autophagosome formation), p62 (autophagosome cargo receptor) and Beclin 1 (regulation of autophagy initiation), were assessed in the left ventricle (LV), right ventricle (RV), left circumflex artery (LCX), right coronary artery (RCA), deltoid, and long head of the triceps (TLH). We found no changes in autophagic markers (LC3B‐I, LC3B‐II, LC3B‐II/I ratio, p62, and Beclin 1) in LV, RV, LCX, RCA, deltoid, and TLH when comparing HF group with CON group (p>0.05). Similarly, ET of any intensity did not alter autophagic markers in LV, RV, LCX, RCA, deltoid, and TLH compared to CON and HF groups (p>0.05). Contrary to our hypothesis, protein levels of a number of different well‐established markers of autophagy were not decreased in the HF group. Further, our results do not demonstrate any change in this important cellular recycling mechanism following chronic low‐intensity ET. Although activation of autophagy is considered a positive adaptation of ET in a setting of physiological health, these data suggest autophagy may not be a mechanism by which ET of an intensity tolerable to a heart failure patient improves cardiovascular and skeletal muscle health in a pre‐clinical model of pressure overload‐induced HF.Support or Funding InformationCraig A. Emter – NIH/NHLBI R01 HL112998, and Kleiton A. S. Silva – AHA: 18POST33960472