| First Author | Palmer BM | Year | 2013 |
| Journal | J Mol Cell Cardiol | Volume | 57 |
| Pages | 23-31 | PubMed ID | 23313350 |
| Mgi Jnum | J:213259 | Mgi Id | MGI:5583950 |
| Doi | 10.1016/j.yjmcc.2012.12.022 | Citation | Palmer BM, et al. (2013) Elevated rates of force development and MgATP binding in F764L and S532P myosin mutations causing dilated cardiomyopathy. J Mol Cell Cardiol 57:23-31 |
| abstractText | Dilated cardiomyopathy (DCM) is a disease characterized by dilation of the ventricular chambers and reduced contractile function. We examined the contractile performance of chemically-skinned ventricular strips from two heterozygous murine models of DCM-causing missense mutations of myosin, F764L/+ and S532P/+, in an alpha-myosin heavy chain (MyHC) background. In Ca(2+)-activated skinned myocardial strips, the maximum developed tension in F764L/+ was only ~50% that of litter-mate controls (+/+). The F764L/+ also exhibited significantly reduced rigor stiffness, loaded shortening velocity and power output. Corresponding indices for S532P/+ strips were not different from controls. Manipulation of MgATP concentration in conjunction with measures of viscoelasticity, which provides estimates of myosin detachment rate 2pic, allowed us to probe the molecular basis of changes in crossbridge kinetics that occur with the myosin mutations. By examining the response of detachment rate to varying MgATP we found the rate of MgADP release was unaffected by the myosin mutations. However, MgATP binding rate was higher in the DCM groups compared to controls (422+/-109mM(-1).s(-1) in F764L/+, 483+/-74mM(-1).s(-1) in S532P/+ and 303+/-18mM(-1).s(-1) in +/+). In addition, the rate constant of force development, 2pib, was significantly higher in DCM groups compared to controls (at 5mM MgATP: 36.9+/-4.9s(-1) in F764L/+, 32.9+/-4.5s(-1) in S532P/+ and 18.2+/-1.7s(-1) in +/+). These results suggest that elevated rates of force development and MgATP binding are features of cardiac myofilament function that underlie the development of DCM. |
