| First Author | Mickelson AV | Year | 2017 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 312 |
| Issue | 1 | Pages | H141-H149 |
| PubMed ID | 27769999 | Mgi Jnum | J:308183 |
| Mgi Id | MGI:6725993 | Doi | 10.1152/ajpheart.00487.2016 |
| Citation | Mickelson AV, et al. (2017) Cardiomyopathy-related mutation (A30V) in mouse cardiac troponin T divergently alters the magnitude of stretch activation in alpha- and beta-myosin heavy chain fibers. Am J Physiol Heart Circ Physiol 312(1):H141-H149 |
| abstractText | 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 NH2 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 alpha- and beta-myosin heavy chain (MHC) isoforms differently alter the functional effect of the NH2 terminus of TnT, we hypothesized that the A28V-induced effects would be differently modulated by alpha- and beta-MHC isoforms. Recombinant wild-type mouse TnT (TnTWT) and the mouse equivalent of the human A28V mutation (TnTA30V) were reconstituted into detergent-skinned cardiac muscle fibers extracted from normal (alpha-MHC) and transgenic (beta-MHC) mice. Dynamic and steady-state contractile parameters were measured in reconstituted muscle fibers. Step-like length perturbation experiments demonstrated that TnTA30V decreased the magnitude of the muscle length-mediated recruitment of new force-bearing cross bridges (ER) by 30% in alpha-MHC fibers. In sharp contrast, TnTA30V increased ER by 55% in beta-MHC fibers. Inferences drawn from other dynamic contractile parameters suggest that directional changes in ER in TnTA30V + alpha-MHC and TnTA30V + beta-MHC fibers result from a divergent impact on cross bridge-regulatory unit (troponin-tropomyosin complex) cooperativity. TnTA30V-mediated effects on Ca(2+)-activated maximal tension and instantaneous muscle fiber stiffness (ED) were also divergently affected by alpha- and beta-MHC. Our study demonstrates that TnTA30V + alpha-MHC and TnTA30V + beta-MHC fibers show contrasting contractile phenotypes; however, only the observations from beta-MHC fibers are consistent with the clinical data for A28V in humans. NEW & NOTEWORTHY: The differential impact of alpha- and beta-myosin heavy chain (MHC) on contractile dynamics causes a mutant cardiac troponin T (TnTA30V) to differently modulate cardiac contractile function. TnTA30V attenuated Ca(2+)-activated maximal tension and length-mediated cross-bridge recruitment against alpha-MHC but augmented these parameters against beta-MHC, suggesting divergent contractile phenotypes. |
