Runx1 is sufficient but not required for cardiomyocyte cell-cycle activation. Am J Physiol Heart Circ Physiol 2024 Aug 01;327(2):H377-H389
Date
06/07/2024Pubmed ID
38847758DOI
10.1152/ajpheart.00782.2023Scopus ID
2-s2.0-85199812831 (requires institutional sign-in at Scopus site)Abstract
Factors responsible for cardiomyocyte proliferation could serve as potential therapeutics to stimulate endogenous myocardial regeneration following insult, such as ischemic injury. A previously published forward genetics approach on cardiomyocyte cell cycle and ploidy led us to the transcription factor, Runx1. Here, we examine the effect of Runx1 on cardiomyocyte cell cycle during postnatal development and cardiac regeneration using cardiomyocyte-specific gain- and loss-of-function mouse models. RUNX1 is expressed in cardiomyocytes during early postnatal life, decreases to negligible levels by 3 wk of age, and increases upon myocardial injury, all consistent with observed rates of cardiomyocyte cell-cycle activity. Loss of Runx1 transiently stymied cardiomyocyte cell-cycle activity during normal postnatal development, a result that corrected itself and did not extend to the context of neonatal heart regeneration. On the other hand, cardiomyocyte-specific Runx1 overexpression resulted in an expansion of diploid cardiomyocytes in uninjured hearts and expansion of 4 N cardiomyocytes in the context of neonatal cardiac injury, suggesting Runx1 overexpression is sufficient to induce cardiomyocyte cell-cycle responses. Persistent overexpression of Runx1 for >1 mo continued to promote cardiomyocyte cell-cycle activity resulting in substantial hyperpolyploidization (≥8 N DNA content). This persistent cell-cycle activation was accompanied by ventricular dilation and adverse remodeling, raising the concern that continued cardiomyocyte cell cycling can have detrimental effects.NEW & NOTEWORTHY Runx1 is sufficient but not required for cardiomyocyte cell cycle.
Author List
Akins KA, Flinn MA, Swift SK, Chanjeevaram SV, Purdy AL, Buddell T, Kolell ME, Andresen KG, Paddock S, Buday SL, Veldman MB, O'Meara CC, Patterson MAuthors
Michael Andrew Flinn Research Scientist I in the Physiology department at Medical College of WisconsinMatthew B. Veldman PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAnimals, Newborn
Cell Cycle
Cell Proliferation
Core Binding Factor Alpha 2 Subunit
Mice
Mice, Inbred C57BL
Myocytes, Cardiac
Polyploidy
Regeneration
