| First Author | Gollapudi SK | Year | 2015 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 308 |
| Issue | 8 | Pages | H884-93 |
| PubMed ID | 25681424 | Mgi Jnum | J:220739 |
| Mgi Id | MGI:5636084 | Doi | 10.1152/ajpheart.00528.2014 |
| Citation | Gollapudi SK, et al. (2015) The functional effect of dilated cardiomyopathy mutation (R144W) in mouse cardiac troponin T is differently affected by alpha- and beta-myosin heavy chain isoforms. Am J Physiol Heart Circ Physiol 308(8):H884-93 |
| abstractText | Given the differential impact of alpha- and beta-myosin heavy chain (MHC) isoforms on how troponin T (TnT) modulates contractile dynamics, we hypothesized that the effects of dilated cardiomyopathy (DCM) mutations in TnT would be altered differently by alpha- and beta-MHC. We characterized dynamic contractile features of normal (alpha-MHC) and transgenic (beta-MHC) mouse cardiac muscle fibers reconstituted with a mouse TnT analog (TnTR144W) of the human DCM R141W mutation. TnTR144W did not alter maximal tension but attenuated myofilament Ca(2+) sensitivity (pCa50) to a similar extent in alpha- and beta-MHC fibers. TnTR144W attenuated the speed of cross-bridge (XB) distortion dynamics (c) by 24% and the speed of XB recruitment dynamics (b) by 17% in alpha-MHC fibers; however, both b and c remained unaltered in beta-MHC fibers. Likewise, TnTR144W attenuated the rates of XB detachment (g) and tension redevelopment (ktr) only in alpha-MHC fibers. TnTR144W also decreased the impact of strained XBs on the recruitment of new XBs (gamma) by 30% only in alpha-MHC fibers. Because c, b, g, ktr, and gamma are strongly influenced by thin filament-based cooperative mechanisms, we conclude that the TnTR144W- and beta-MHC-mediated changes in the thin filament interact to produce a less severe functional phenotype, compared with that brought about by TnTR144W and alpha-MHC. These observations provide a basis for lower mortality rates of humans (beta-MHC) harboring the TnTR141W mutant compared with transgenic mouse studies. Our findings strongly suggest that some caution is necessary when extrapolating data from transgenic mouse studies to human hearts. |
