4.7 Article

Muscarinic receptors promote pacemaker fate at the expense of secondary conduction system tissue in zebrafish

期刊

JCI INSIGHT
卷 4, 期 20, 页码 -

出版社

AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.121971

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资金

  1. Boehringer Ingelheim Ulm University BioCenter
  2. NIH [HL105414, U01HL099997]
  3. American Heart Association [17SDG33400114]
  4. German Excellence Initiative of the DFG
  5. DFG [PH144/4-1, PH144/6-1]
  6. Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (Bethesda, Maryland, USA)
  7. DZHK, the German Federal Ministry for Science and Education [BMBF FKZ 13GW0007A [CIRM-ET3]]
  8. German Research Foundation [DFG ZI 708/10-1, SFB 937 TP18, SFB 1002 TPs C04, IRTG 1816 RP12]
  9. Foundation Leducq

向作者/读者索取更多资源

Deterioration or inborn malformations of the cardiac conduction system (CCS) interfere with proper impulse propagation in the heart and may lead to sudden cardiac death or heart failure. Patients afflicted with arrhythmia depend on antiarrhythmic medication or invasive therapy, such as pacemaker implantation. An ideal way to treat these patients would be CCS tissue restoration. This, however, requires precise knowledge regarding the molecular mechanisms underlying CCS development. Here, we aimed to identify regulators of CCS development. We performed a compound screen in zebrafish embryos and identified tolterodine, a muscarinic receptor antagonist, as a modifier of CCS development. Tolterodine provoked a lower heart rate, pericardiac edema, and arrhythmia. Blockade of muscarinic M3, but not M2, receptors induced transcriptional changes leading to amplification of sinoatrial cells and loss of atrioventricular identity. Transcriptome data from an engineered human heart muscle model provided additional evidence for the contribution of muscarinic M3 receptors during cardiac progenitor specification and differentiation. Taken together, we found that muscarinic M3 receptors control the CCS already before the heart becomes innervated. Our data indicate that muscarinic receptors maintain a delicate balance between the developing sinoatrial node and the atrioventricular canal, which is probably required to prevent the development of arrhythmia.

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