{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T23:43:05Z","timestamp":1790120585866,"version":"4.0.1"},"reference-count":47,"publisher":"American Physiological Society","issue":"1","funder":[{"DOI":"10.13039\/501100000850","name":"National Heart and Lung Institute (NHLI)","doi-asserted-by":"publisher","award":["HL-075643"],"award-info":[{"award-number":["HL-075643"]}],"id":[{"id":"10.13039\/501100000850","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2017,1,1]]},"abstract":"<jats:p>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<jats:sub>2<\/jats:sub>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 \u03b1- and \u03b2-myosin heavy chain (MHC) isoforms differently alter the functional effect of the NH<jats:sub>2<\/jats:sub>terminus of TnT, we hypothesized that the A28V-induced effects would be differently modulated by \u03b1- and \u03b2-MHC isoforms. Recombinant wild-type mouse TnT (TnT<jats:sub>WT<\/jats:sub>) and the mouse equivalent of the human A28V mutation (TnT<jats:sub>A30V<\/jats:sub>) were reconstituted into detergent-skinned cardiac muscle fibers extracted from normal (\u03b1-MHC) and transgenic (\u03b2-MHC) mice. Dynamic and steady-state contractile parameters were measured in reconstituted muscle fibers. Step-like length perturbation experiments demonstrated that TnT<jats:sub>A30V<\/jats:sub>decreased the magnitude of the muscle length-mediated recruitment of new force-bearing cross bridges ( E<jats:sub>R<\/jats:sub>) by 30% in \u03b1-MHC fibers. In sharp contrast, TnT<jats:sub>A30V<\/jats:sub>increased E<jats:sub>R<\/jats:sub>by 55% in \u03b2-MHC fibers. Inferences drawn from other dynamic contractile parameters suggest that directional changes in E<jats:sub>R<\/jats:sub>in TnT<jats:sub>A30V<\/jats:sub>+ \u03b1-MHC and TnT<jats:sub>A30V<\/jats:sub>+ \u03b2-MHC fibers result from a divergent impact on cross bridge-regulatory unit (troponin-tropomyosin complex) cooperativity. TnT<jats:sub>A30V<\/jats:sub>-mediated effects on Ca<jats:sup>2+<\/jats:sup>-activated maximal tension and instantaneous muscle fiber stiffness ( E<jats:sub>D<\/jats:sub>) were also divergently affected by \u03b1- and \u03b2-MHC. Our study demonstrates that TnT<jats:sub>A30V<\/jats:sub>+ \u03b1-MHC and TnT<jats:sub>A30V<\/jats:sub>+ \u03b2-MHC fibers show contrasting contractile phenotypes; however, only the observations from \u03b2-MHC fibers are consistent with the clinical data for A28V in humans.<\/jats:p><jats:p>NEW &amp; NOTEWORTHY The differential impact of \u03b1- and \u03b2-myosin heavy chain (MHC) on contractile dynamics causes a mutant cardiac troponin T (TnT<jats:sub>A30V<\/jats:sub>) to differently modulate cardiac contractile function. TnT<jats:sub>A30V<\/jats:sub>attenuated Ca<jats:sup>2+<\/jats:sup>-activated maximal tension and length-mediated cross-bridge recruitment against \u03b1-MHC but augmented these parameters against \u03b2-MHC, suggesting divergent contractile phenotypes.<\/jats:p>","DOI":"10.1152\/ajpheart.00487.2016","type":"journal-article","created":{"date-parts":[[2016,10,22]],"date-time":"2016-10-22T03:45:43Z","timestamp":1477107943000},"page":"H141-H149","source":"Crossref","is-referenced-by-count":5,"title":["Cardiomyopathy-related mutation (A30V) in mouse cardiac troponin T divergently alters the magnitude of stretch activation in \u03b1- and \u03b2-myosin heavy chain fibers"],"prefix":"10.1152","volume":"312","author":[{"given":"Alexis V.","family":"Mickelson","sequence":"first","affiliation":[{"name":"Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sampath 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