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The present study investigated the functional consequences of the human hypertrophic cardiomyopathy (HCM) mutation A28V in cardiac troponin T (TnT). The A28V mutation is located within the NH 2  terminus of TnT, a region known to be important for full activation of cardiac thin filaments. The functional consequences of the A28V mutation in TnT remain unknown. Given how α- and β-myosin heavy chain (MHC) isoforms differently alter the functional effect of the NH 2  terminus of TnT, we hypothesized that the A28V-induced effects would be differently modulated by α- and β-MHC isoforms. Recombinant wild-type mouse TnT (TnT WT ) and the mouse equivalent of the human A28V mutation (TnT A30V ) were reconstituted into detergent-skinned cardiac muscle fibers extracted from normal (α-MHC) and transgenic (β-MHC) mice. Dynamic and steady-state contractile parameters were measured in reconstituted muscle fibers. Step-like length perturbation experiments demonstrated that TnT A30V  decreased the magnitude of the muscle length-mediated recruitment of new force-bearing cross bridges ( E R ) by 30% in α-MHC fibers. In sharp contrast, TnT A30V  increased E R  by 55% in β-MHC fibers. Inferences drawn from other dynamic contractile parameters suggest that directional changes in E R  in TnT A30V  + α-MHC and TnT A30V  + β-MHC fibers result from a divergent impact on cross bridge-regulatory unit (troponin-tropomyosin complex) cooperativity. TnT A30V -mediated effects on Ca 2+ -activated maximal tension and instantaneous muscle fiber stiffness ( E D ) were also divergently affected by α- and β-MHC. Our study demonstrates that TnT A30V  + α-MHC and TnT A30V  + β-MHC fibers show contrasting contractile phenotypes; however, only the observations from β-MHC fibers are consistent with the clinical data for A28V in humans.    NEW &amp; NOTEWORTHY The differential impact of α- and β-myosin heavy chain (MHC) on contractile dynamics causes a mutant cardiac troponin T (TnT A30V ) to differently modulate cardiac contractile function. TnT A30V  attenuated Ca 2+ -activated maximal tension and length-mediated cross-bridge recruitment against α-MHC but augmented these parameters against β-MHC, suggesting divergent contractile phenotypes.

american journal of physiology. heart and circulatory physiology

Cardiomyopathy-related mutation (A30V) in mouse cardiac troponin T divergently alters the magnitude of stretch activation in α- and β-myosin heavy chain fibers