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/wk for 14 wk) 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 with 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 with that in sedentary swine. Fibronectin- and exercise-induced force generation in trabeculae from collateral-dependent myocardium was 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.NEW & NOTEWORTHY Exercise produces cardioprotective effects and reverses cardiac dysfunction, but underlying cellular and molecular mechanisms are not fully identified. This study revealed that endurance exercise increased fibronectin expression in the myocardium of ischemic swine hearts and enhanced myocyte adhesion with α(5)β(1) integrin, cell stiffness, and force generation, which was blunted by focal adhesion kinase inhibition. Thus, endurance exercise reverses cardiac dysfunction by promoting fibronectin interactions with integrins supporting this mechanotransduction pathway as a potential therapeutic target.