Fibronectin increases the force production of mouse papillary muscles via α5β1 integrin
- Additional Document Info
- View All
The extracellular matrix (ECM) protein-integrin-cytoskeleton axis plays a central role as a mechanotransducing protein assemblage in many cell types. However, how the process of mechanotransduction and the mechanically generated signals arising from this axis affect myofilament function in cardiac muscle are not completely understood. We hypothesize that ECM proteins can regulate cardiac function through integrin binding, and thereby alter the intracellular calcium concentration ([Ca(2+)](i)) and/or modulate myofilament activation processes. Force measurements made in mouse papillary muscle demonstrated that in the presence of the soluble form of the ECM protein, fibronectin (FN), active force was increased significantly by 40% at 1 Hz, 54% at 2 Hz, 35% at 5 Hz and 16% at 9 Hz stimulation frequencies. Furthermore, increased active force in the presence of FN was associated with 12-33% increase in [Ca(2+)](i) and 20-50% increase in active force per unit Ca(2+). A function blocking antibody for α5 integrin prevented the effects of the FN on the changes in force and [Ca(2+)](i), whereas a function blocking α3 integrin antibody did not reverse the effects of FN. The effects of FN were reversed by an L-type Ca(2+) channel blocker, verapamil or PKA inhibitor. Freshly isolated cardiomyocytes exhibited a 39% increase in contraction force and a 36% increase in L-type Ca(2+) current in the presence of FN. Fibers treated with FN showed a significant increase in the phosphorylation of phospholamban; however, the phosphorylation of troponin I was unchanged. These results demonstrate that FN acts via α5β1 integrin to increase force production in myocardium and that this effect is partly mediated by increases in [Ca(2+)](i) and Ca(2+) sensitivity, PKA activation and phosphorylation of phospholamban.
author list (cited authors)
Wu, X., Chakraborty, S., Heaps, C. L., Davis, M. J., Meininger, G. A., & Muthuchamy, M.