{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:36:56Z","timestamp":1753889816413,"version":"3.41.2"},"reference-count":53,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2016,3,9]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              We hypothesized that the functional effects of R206L\u2014a rat analog of the dilated cardiomyopathy (\n              <jats:styled-content style=\"fixed-case\">DCM<\/jats:styled-content>\n              ) mutation R205L in human cardiac troponin T (TnT)\u2014were differently modulated by myosin heavy chain (\n              <jats:styled-content style=\"fixed-case\">MHC<\/jats:styled-content>\n              ) isoforms and T204E, a protein kinase C (\n              <jats:styled-content style=\"fixed-case\">PKC<\/jats:styled-content>\n              ) phosphomimic of TnT. Our hypothesis was based on two observations: (1) \u03b1\u2010 and \u03b2\u2010\n              <jats:styled-content style=\"fixed-case\">MHC<\/jats:styled-content>\n              differentially influence the functional effects of TnT; and (2)\n              <jats:styled-content style=\"fixed-case\">PKC<\/jats:styled-content>\n              isoforms capable of phosphorylating TnT are upregulated in failing human hearts.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              We generated 4 recombinant TnT variants: wild type; R206L; T204E; and R206L+T204E. Functional effects of the TnT variants were tested in cardiac muscle fibers (minimum 14 per group) from normal (\u03b1\u2010\n              <jats:styled-content style=\"fixed-case\">MHC<\/jats:styled-content>\n              ) and propylthiouracil\u2010treated rats (\u03b2\u2010\n              <jats:styled-content style=\"fixed-case\">MHC<\/jats:styled-content>\n              ) using steady\u2010state and dynamic contractile measurements. Notably, in \u03b1\u2010\n              <jats:styled-content style=\"fixed-case\">MHC<\/jats:styled-content>\n              fibers, Ca\n              <jats:sup>2+<\/jats:sup>\n              \u2010activated maximal tension was attenuated by R206L (\u224832%), T204E (\u224863%), and R206L+T204E (\u224864%). In \u03b2\u2010\n              <jats:styled-content style=\"fixed-case\">MHC<\/jats:styled-content>\n              fibers, maximal tension was unaffected by R206L, but was attenuated by T204E (\u224833%) and R206L+T204E (\u224840%). Thus, \u03b2\u2010\n              <jats:styled-content style=\"fixed-case\">MHC<\/jats:styled-content>\n              differentially counteracted the attenuating effects of the TnT variants on tension. However, in \u03b2\u2010\n              <jats:styled-content style=\"fixed-case\">MHC<\/jats:styled-content>\n              fibers, R206L+T204E attenuated tension to a greater extent when compared to T204E alone. In \u03b2\u2010\n              <jats:styled-content style=\"fixed-case\">MHC<\/jats:styled-content>\n              fibers, R206L+T204E attenuated the magnitude of the length\u2010mediated recruitment of new cross\u2010bridges (\u224828%), suggesting that the Frank\u2010Starling mechanism was impaired.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Our findings are the first (to our knowledge) to demonstrate that the functional effects of a\n              <jats:styled-content style=\"fixed-case\">DCM<\/jats:styled-content>\n              \u2010linked TnT mutation are not only modulated by\n              <jats:styled-content style=\"fixed-case\">MHC<\/jats:styled-content>\n              isoforms, but also by the pathology\u2010associated post\u2010translational modifications of TnT.\n            <\/jats:p>\n          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