Medical College of Wisconsin
CTSICores SearchResearch InformaticsREDCap

Tnni3k alleles influence ventricular mononuclear diploid cardiomyocyte frequency. PLoS Genet 2019 10;15(10):e1008354

Date

10/08/2019

Pubmed ID

31589606

Pubmed Central ID

PMC6797218

DOI

10.1371/journal.pgen.1008354

Abstract

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.

Author List

Gan P, Patterson M, Velasquez A, Wang K, Tian D, Windle JJ, Tao G, Judge DP, Makita T, Park TJ, Sucov HM

Author

Michaela Patterson 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

Alleles
Animals
Cell Differentiation
Cell Lineage
Cell Proliferation
Evolution, Molecular
Heart Diseases
Heart Ventricles
Humans
Loss of Function Mutation
Mice
Mole Rats
Myocardium
Myocytes, Cardiac
Oxidative Stress
Polyploidy
Protein-Serine-Threonine Kinases
Regeneration