The functional effect of dilated cardiomyopathy mutation (R144W) in mouse cardiac troponin T is differently affected by α- and β-myosin heavy chain isoforms

Given the differential impact of α- and β-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 α- and β-MHC. We characterized dynamic contractile features of normal (α-MHC) and transgenic (β-MHC) mouse cardiac muscle fibers reconstituted with a mouse TnT analog (TnT_R144W) of the human DCM R141W mutation. TnT_R144W did not alter maximal tension but attenuated myofilament Ca²⁺ sensitivity (pCa₅₀) to a similar extent in α- and β-MHC fibers. TnT_R144W attenuated the speed of cross-bridge (XB) distortion dynamics (c) by 24% and the speed of XB recruitment dynamics (b) by 17% in α-MHC fibers; however, both b and c remained unaltered in β-MHC fibers. Likewise, TnT_R144W attenuated the rates of XB detachment (g) and tension redevelopment (k_tr) only in α-MHC fibers. TnT_R144W also decreased the impact of strained XBs on the recruitment of new XBs (γ) by 30% only in α-MHC fibers. Because c, b, g, k_tr, and γ are strongly influenced by thin filament-based cooperative mechanisms, we conclude that the TnT_R144W- and β-MHC-mediated changes in the thin filament interact to produce a less severe functional phenotype, compared with that brought about by TnT_R144Wand α-MHC. These observations provide a basis for lower mortality rates of humans (β-MHC) harboring the TnT_R141W 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.