{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T23:55:34Z","timestamp":1791330934736,"version":"4.3.1"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2008,10,24]]},"abstract":"<jats:p>\n                    Normal cardiac function requires dynamic modulation of contraction. \u03b21-Adrenergic\u2013induced protein kinase (PK)A phosphorylation of cardiac myosin binding protein (cMyBP)-C may regulate crossbridge kinetics to modulate contraction. We tested this idea with mechanical measurements and echocardiography in a mouse model lacking 3 PKA sites on cMyBP-C, ie, cMyBP-C(t3SA). We developed the model by transgenic expression of mutant cMyBP-C with Ser-to-Ala mutations on the cMyBP-C knockout background. Western blots, immunofluorescence, and in vitro phosphorylation combined to show that non\u2013PKA-phosphorylatable cMyBP-C expressed at 74% compared to normal wild-type (WT) and was correctly positioned in the sarcomeres. Similar expression of WT cMyBP-C at 72% served as control, ie, cMyBP-C(tWT). Skinned myocardium responded to stretch with an immediate increase in force, followed by a transient relaxation of force and finally a delayed development of force, ie, stretch activation. The rate constants of relaxation,\n                    <jats:italic>k<\/jats:italic>\n                    <jats:sub>rel<\/jats:sub>\n                    (s-1), and delayed force development,\n                    <jats:italic>k<\/jats:italic>\n                    <jats:sub>df<\/jats:sub>\n                    (s-1), in the stretch activation response are indicators of crossbridge cycling kinetics. cMyBP-C(t3SA) myocardium had baseline\n                    <jats:italic>k<\/jats:italic>\n                    <jats:sub>rel<\/jats:sub>\n                    and\n                    <jats:italic>k<\/jats:italic>\n                    <jats:sub>df<\/jats:sub>\n                    similar to WT myocardium, but, unlike WT,\n                    <jats:italic>k<\/jats:italic>\n                    <jats:sub>rel<\/jats:sub>\n                    and\n                    <jats:italic>k<\/jats:italic>\n                    <jats:sub>df<\/jats:sub>\n                    were not accelerated by PKA treatment. Reduced dobutamine augmentation of systolic function in cMyBP-C(t3SA) hearts during echocardiography corroborated the stretch activation findings. Furthermore, cMyBP-C(t3SA) hearts exhibited basal echocardiographic findings of systolic dysfunction, diastolic dysfunction, and hypertrophy. Conversely, cMyBP-C(tWT) hearts performed similar to WT. Thus, PKA phosphorylation of cMyBP-C accelerates crossbridge kinetics and loss of this regulation leads to cardiac dysfunction.\n                  <\/jats:p>","DOI":"10.1161\/circresaha.108.177683","type":"journal-article","created":{"date-parts":[[2008,9,18]],"date-time":"2008-09-18T21:39:54Z","timestamp":1221773994000},"page":"974-982","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":180,"title":["Acceleration of Crossbridge Kinetics by Protein Kinase A Phosphorylation of Cardiac Myosin Binding Protein C Modulates Cardiac Function"],"prefix":"10.1161","volume":"103","author":[{"given":"Carl W.","family":"Tong","sequence":"first","affiliation":[{"name":"From the Department of Physiology, University of Wisconsin School of Medicine and Public Health, Madison."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian E.","family":"Stelzer","sequence":"additional","affiliation":[{"name":"From the Department of Physiology, University of Wisconsin School of Medicine and Public Health, Madison."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion L.","family":"Greaser","sequence":"additional","affiliation":[{"name":"From the Department of Physiology, University of Wisconsin School of Medicine and Public Health, Madison."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia A.","family":"Powers","sequence":"additional","affiliation":[{"name":"From the Department of Physiology, University of Wisconsin School of Medicine and Public Health, Madison."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard L.","family":"Moss","sequence":"additional","affiliation":[{"name":"From the Department of Physiology, University of Wisconsin School of Medicine and Public Health, Madison."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_1_2","unstructured":"Zipes DP Libby P Bonow RO Braunwald E. 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