{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:39:12Z","timestamp":1790836752696,"version":"4.1.0"},"reference-count":50,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2016,2,1]],"date-time":"2016-02-01T00:00:00Z","timestamp":1454284800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2016,2]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>\u03b2\u2010adrenergic stimulation increases cardiac myosin binding protein C (MyBP\u2010C) and troponin I phosphorylation to accelerate pressure development and relaxation <jats:italic>in vivo<\/jats:italic>, although their relative contributions remain unknown.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Using a novel mouse model lacking protein kinase A\u2010phosphorylatable troponin I (TnI) and MyBP\u2010C, we examined <jats:italic>in vivo<\/jats:italic> haemodynamic function before and after infusion of the \u03b2\u2010agonist dobutamine.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Mice expressing phospho\u2010ablated MyBP\u2010C displayed cardiac hypertrophy and prevented full acceleration of pressure development and relaxation in response to dobutamine, whereas expression of phosphor\u2010ablated TnI alone had little effect on the acceleration of contractile function in response to dobutamine.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Our data demonstrate that MyBP\u2010C phosphorylation is the principal mediator of the contractile response to increased \u03b2\u2010agonist stimulation <jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These results help us understand why MyBP\u2010C dephosphorylation in the failing heart contributes to contractile dysfunction and decreased adrenergic reserve in response to acute stress.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>\u03b2\u2010adrenergic stimulation plays a critical role in accelerating ventricular contraction and speeding relaxation to match cardiac output to changing circulatory demands. Two key myofilaments proteins, troponin I (TnI) and myosin binding protein\u2010C (MyBP\u2010C), are phosphorylated following \u03b2\u2010adrenergic stimulation; however, their relative contributions to the enhancement of <jats:italic>in vivo<\/jats:italic> cardiac contractility are unknown. To examine the roles of TnI and MyBP\u2010C phosphorylation in \u03b2\u2010adrenergic\u2010mediated enhancement of cardiac function, transgenic (TG) mice expressing non\u2010phosphorylatable TnI protein kinase A (PKA) residues (i.e. serine to alanine substitution at Ser23\/24; TnI<jats:sup>PKA\u2212<\/jats:sup>) were bred with mice expressing non\u2010phosphorylatable MyBP\u2010C PKA residues (i.e. serine to alanine substitution at Ser273, Ser282 and Ser302; MyBPC<jats:sup>PKA\u2212<\/jats:sup>) to generate a novel mouse model expressing non\u2010phosphorylatable PKA residues in TnI and MyBP\u2010C (DBL<jats:sup>PKA\u2212<\/jats:sup>). MyBP\u2010C dephosphorylation produced cardiac hypertrophy and increased wall thickness in MyBPC<jats:sup>PKA\u2212<\/jats:sup> and DBL<jats:sup>PKA\u2212<\/jats:sup> mice, and <jats:italic>in vivo<\/jats:italic> echocardiography and pressure\u2013volume catheterization studies revealed impaired systolic function and prolonged diastolic relaxation compared to wild\u2010type and TnI<jats:sup>PKA\u2013<\/jats:sup> mice. Infusion of the \u03b2\u2010agonist dobutamine resulted in accelerated rates of pressure development and relaxation in all mice; however, MyBPC<jats:sup>PKA\u2212<\/jats:sup> and DBL<jats:sup>PKA\u2212<\/jats:sup> mice displayed a blunted contractile response compared to wild\u2010type and TnI<jats:sup>PKA\u2013<\/jats:sup> mice. Furthermore, unanaesthesized MyBPC<jats:sup>PKA\u2212<\/jats:sup> and DBL<jats:sup>PKA\u2212<\/jats:sup> mice displayed depressed maximum systolic pressure in response to dobutamine as measured using implantable telemetry devices. Taken together, our data show that MyBP\u2010C phosphorylation is a critical modulator of the <jats:italic>in\u00a0vivo<\/jats:italic> acceleration of pressure development and relaxation as a result of enhanced \u03b2\u2010adrenergic stimulation, and reduced MyBP\u2010C phosphorylation may underlie depressed adrenergic reserve in heart failure.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp270959","type":"journal-article","created":{"date-parts":[[2015,12,4]],"date-time":"2015-12-04T10:14:48Z","timestamp":1449224088000},"page":"669-686","source":"Crossref","is-referenced-by-count":47,"title":["The contributions of cardiac myosin binding protein C and troponin I phosphorylation to \u03b2\u2010adrenergic enhancement of <i>in vivo<\/i> cardiac function"],"prefix":"10.1113","volume":"594","author":[{"given":"Kenneth S.","family":"Gresham","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics, School of Medicine Case Western Reserve University  Cleveland OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian E.","family":"Stelzer","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, School of Medicine Case Western Reserve University  Cleveland OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,2]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/clc.4960190513"},{"key":"e_1_2_6_3_1","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1007\/BF00788870","article-title":"Time to dP\/dtmax, a preload\u2010independent index of contractility: open\u2010chest dog study","volume":"91","author":"Adler D","year":"1996","journal-title":"Basic Res 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