Cardiac MyBP-C phosphorylation regulates the Frank–Starling relationship in murine hearts
| العنوان: | Cardiac MyBP-C phosphorylation regulates the Frank–Starling relationship in murine hearts |
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| المؤلفون: | Laurin M. Hanft, Richard L. Moss, Timothy A. Hacker, Daniel P. Fitzsimons, Kerry S. McDonald |
| المصدر: | The Journal of General Physiology |
| بيانات النشر: | Rockefeller University Press, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Sarcomeres, 0301 basic medicine, Myofilament, Contraction and cell motility, Physiology, Mice, Transgenic, Myofilament Special Issue, 2020, 030204 cardiovascular system & hematology, Sarcomere, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, Myosin, Animals, Myocyte, Phosphorylation, Molecular physiology, Frank–Starling law of the heart, Chemistry, Myocardium, Cyclic AMP-Dependent Protein Kinases, Myocardial Contraction, Cell biology, 030104 developmental biology, Starlings, cardiovascular system, Ventricular pressure, Carrier Proteins, Myofibril |
| الوصف: | Cardiac myosin-binding protein C (cMyBP-C) is thought to regulate cardiac muscle and heart contraction. Hanft et al. show that cMyBP-C phosphorylation regulates length dependence of power output in murine permeabilized cardiac myocytes, which translates to in vivo Frank–Starling relationships. The Frank–Starling relationship establishes that elevated end-diastolic volume progressively increases ventricular pressure and stroke volume in healthy hearts. The relationship is modulated by a number of physiological inputs and is often depressed in human heart failure. Emerging evidence suggests that cardiac myosin-binding protein-C (cMyBP-C) contributes to the Frank–Starling relationship. We measured contractile properties at multiple levels of structural organization to determine the role of cMyBP-C and its phosphorylation in regulating (1) the sarcomere length dependence of power in cardiac myofilaments and (2) the Frank–Starling relationship in vivo. We compared transgenic mice expressing wild-type cMyBP-C on the null background, which have ∼50% phosphorylated cMyBP-C (Controls), to transgenic mice lacking cMyBP-C (KO) and to mice expressing cMyBP-C that have serine-273, -282, and -302 mutated to aspartate (cMyBP-C t3SD) or alanine (cMyBP-C t3SA) on the null background to mimic either constitutive PKA phosphorylation or nonphosphorylated cMyBP-C, respectively. We observed a continuum of length dependence of power output in myocyte preparations. Sarcomere length dependence of power progressively increased with a rank ordering of cMyBP-C KO = cMyBP-C t3SA < Control < cMyBP-C t3SD. Length dependence of myofilament power translated, at least in part, to hearts, whereby Frank–Starling relationships were steepest in cMyBP-C t3SD mice. The results support the hypothesis that cMyBP-C and its phosphorylation state tune sarcomere length dependence of myofibrillar power, and these regulatory processes translate across spatial levels of myocardial organization to control beat-to-beat ventricular performance. |
| تدمد: | 1540-7748 0022-1295 |
| DOI: | 10.1085/jgp.202012770 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a6aba5c9d76ed4ea68c2dd395512ccca https://doi.org/10.1085/jgp.202012770 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....a6aba5c9d76ed4ea68c2dd395512ccca |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15407748 00221295 |
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| DOI: | 10.1085/jgp.202012770 |