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Tnni3k alleles influence ventricular mononuclear diploid cardiomyocyte frequency

Recent evidence implicates mononuclear diploid cardiomyocytes as a proliferative and regenerative subpopulation of the postnatal heart. The number of these cardiomyocytes is a complex trait showing substantial natural variation among inbred mouse strains based on the combined influences of multiple...

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Autores principales: Gan, Peiheng, Patterson, Michaela, Velasquez, Alexa, Wang, Kristy, Tian, Di, Windle, Jolene J., Tao, Ge, Judge, Daniel P., Makita, Takako, Park, Thomas J., Sucov, Henry M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797218/
https://www.ncbi.nlm.nih.gov/pubmed/31589606
http://dx.doi.org/10.1371/journal.pgen.1008354
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author Gan, Peiheng
Patterson, Michaela
Velasquez, Alexa
Wang, Kristy
Tian, Di
Windle, Jolene J.
Tao, Ge
Judge, Daniel P.
Makita, Takako
Park, Thomas J.
Sucov, Henry M.
author_facet Gan, Peiheng
Patterson, Michaela
Velasquez, Alexa
Wang, Kristy
Tian, Di
Windle, Jolene J.
Tao, Ge
Judge, Daniel P.
Makita, Takako
Park, Thomas J.
Sucov, Henry M.
author_sort Gan, Peiheng
collection PubMed
description Recent evidence implicates mononuclear diploid cardiomyocytes as a proliferative and regenerative subpopulation of the postnatal heart. The number of these cardiomyocytes is a complex trait showing substantial natural variation among inbred mouse strains based on the combined influences of multiple polymorphic genes. One gene confirmed to influence this parameter is the cardiomyocyte-specific kinase Tnni3k. Here, we have studied Tnni3k alleles across a number of species. Using a newly-generated kinase-dead allele in mice, we show that Tnni3k function is dependent on its kinase activity. In an in vitro kinase assay, we show that several common human TNNI3K kinase domain variants substantially compromise kinase activity, suggesting that TNNI3K may influence human heart regenerative capacity and potentially also other aspects of human heart disease. We show that two kinase domain frameshift mutations in mice cause loss-of-function consequences by nonsense-mediated decay. We further show that the Tnni3k gene in two species of mole-rat has independently devolved into a pseudogene, presumably associated with the transition of these species to a low metabolism and hypoxic subterranean life. This may be explained by the observation that Tnni3k function in mice converges with oxidative stress to regulate mononuclear diploid cardiomyocyte frequency. Unlike other studied rodents, naked mole-rats have a surprisingly high (30%) mononuclear cardiomyocyte level but most of their mononuclear cardiomyocytes are polyploid; their mononuclear diploid cardiomyocyte level (7%) is within the known range (2–10%) of inbred mouse strains. Naked mole-rats provide further insight on a recent proposal that cardiomyocyte polyploidy is associated with evolutionary acquisition of endothermy.
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spelling pubmed-67972182019-10-25 Tnni3k alleles influence ventricular mononuclear diploid cardiomyocyte frequency Gan, Peiheng Patterson, Michaela Velasquez, Alexa Wang, Kristy Tian, Di Windle, Jolene J. Tao, Ge Judge, Daniel P. Makita, Takako Park, Thomas J. Sucov, Henry M. PLoS Genet Research Article Recent evidence implicates mononuclear diploid cardiomyocytes as a proliferative and regenerative subpopulation of the postnatal heart. The number of these cardiomyocytes is a complex trait showing substantial natural variation among inbred mouse strains based on the combined influences of multiple polymorphic genes. One gene confirmed to influence this parameter is the cardiomyocyte-specific kinase Tnni3k. Here, we have studied Tnni3k alleles across a number of species. Using a newly-generated kinase-dead allele in mice, we show that Tnni3k function is dependent on its kinase activity. In an in vitro kinase assay, we show that several common human TNNI3K kinase domain variants substantially compromise kinase activity, suggesting that TNNI3K may influence human heart regenerative capacity and potentially also other aspects of human heart disease. We show that two kinase domain frameshift mutations in mice cause loss-of-function consequences by nonsense-mediated decay. We further show that the Tnni3k gene in two species of mole-rat has independently devolved into a pseudogene, presumably associated with the transition of these species to a low metabolism and hypoxic subterranean life. This may be explained by the observation that Tnni3k function in mice converges with oxidative stress to regulate mononuclear diploid cardiomyocyte frequency. Unlike other studied rodents, naked mole-rats have a surprisingly high (30%) mononuclear cardiomyocyte level but most of their mononuclear cardiomyocytes are polyploid; their mononuclear diploid cardiomyocyte level (7%) is within the known range (2–10%) of inbred mouse strains. Naked mole-rats provide further insight on a recent proposal that cardiomyocyte polyploidy is associated with evolutionary acquisition of endothermy. Public Library of Science 2019-10-07 /pmc/articles/PMC6797218/ /pubmed/31589606 http://dx.doi.org/10.1371/journal.pgen.1008354 Text en © 2019 Gan et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Gan, Peiheng
Patterson, Michaela
Velasquez, Alexa
Wang, Kristy
Tian, Di
Windle, Jolene J.
Tao, Ge
Judge, Daniel P.
Makita, Takako
Park, Thomas J.
Sucov, Henry M.
Tnni3k alleles influence ventricular mononuclear diploid cardiomyocyte frequency
title Tnni3k alleles influence ventricular mononuclear diploid cardiomyocyte frequency
title_full Tnni3k alleles influence ventricular mononuclear diploid cardiomyocyte frequency
title_fullStr Tnni3k alleles influence ventricular mononuclear diploid cardiomyocyte frequency
title_full_unstemmed Tnni3k alleles influence ventricular mononuclear diploid cardiomyocyte frequency
title_short Tnni3k alleles influence ventricular mononuclear diploid cardiomyocyte frequency
title_sort tnni3k alleles influence ventricular mononuclear diploid cardiomyocyte frequency
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797218/
https://www.ncbi.nlm.nih.gov/pubmed/31589606
http://dx.doi.org/10.1371/journal.pgen.1008354
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