Exercise training ameliorates myocardial dysfunction through fibronectin mediated mechanotransduction in a swine model of ischemic heart disease

Exercise training has been shown to reverse cardiac dysfunction in patients and animal models of coronary artery disease; however, the underlying mechanisms have not been fully elucidated. Transmembrane integrins that connect the extracellular matrix (ECM) and intracellular cytoskeleton are important for mechanotransduction in cardiomyocytes. We tested the hypothesis that exercise training would increase cardiac contractile function by modulating the adhesion force between integrins and ECM proteins and subsequent cell signaling and stiffness in myocytes from ischemic porcine hearts. Ameroid occluders were surgically placed around the proximal left circumflex coronary artery of adult Yucatan pigs. Animals subsequently completed either a sedentary or endurance exercise (treadmill run 5 days/week for 14 weeks) protocol, after which myocardium was isolated from nonoccluded and collateral-dependent regions. The collateral-dependent myocardial region exhibited increased fibrosis, inflammatory cytokines, and collagen I and III levels, which were ameliorated with exercise-training. Exercise also increased fibronectin and β1 integrin, and decreased β3 integrin levels in collateral-dependent myocardium compared to that of sedentary pigs. Atomic force microscopy revealed that an increase in fibronectin-integrin adhesion force was mediated by α 5 β 1 and α v β 3 integrins in cardiac myocytes of exercise-trained pigs. Exercise training increased mechanical stiffness in cardiomyocytes compared to that in sedentary swine. Fibronectin- and exercise-induced force generation in trabeculae from collateral-dependent myocardium were each decreased by focal adhesion kinase (FAK) inhibition. These data demonstrate that exercise training increases force generation in cardiomyocytes by attenuating inflammation and by promoting fibronectin mediated FAK activation, suggesting potential targeting of this mechanotransduction pathway for therapeutic development.