Tnni3k alleles influence ventricular mononuclear diploid cardiomyocyte frequency


Autoři: Peiheng Gan aff001;  Michaela Patterson aff004;  Alexa Velasquez aff003;  Kristy Wang aff001;  Di Tian aff005;  Jolene J. Windle aff006;  Ge Tao aff001;  Daniel P. Judge aff002;  Takako Makita aff007;  Thomas J. Park aff008;  Henry M. Sucov aff001
Působiště autorů: Department of Regenerative Medicine and Cell Biology, Medical Univ. South Carolina, Charleston, South Carolina, United States of America aff001;  Department of Medicine, Division of Cardiology, Medical University of South Carolina, Charleston, South Carolina, United States of America aff002;  Department of Regenerative Medicine and Stem Cell Biology, University of Southern California Keck School of Medicine, Los Angeles, California, United States of America aff003;  Department of Cell Biology, Neurobiology and Anatomy, and Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America aff004;  Department of Pathology and Laboratory Medicine, Tulane Univeristy School of Medicine, New Orleans, Louisiana, United States of America aff005;  Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virgina, United States of America aff006;  Darby Children’s Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina, United States of America aff007;  Laboratory of Integrative Neuroscience, Department of Biological Sciences, University of Illinois at Chicago, Chicago, Illinois, United States of America aff008
Vyšlo v časopise: Tnni3k alleles influence ventricular mononuclear diploid cardiomyocyte frequency. PLoS Genet 15(10): e32767. doi:10.1371/journal.pgen.1008354
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008354

Souhrn

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.

Klíčová slova:

Alleles – Mammalian genomics – Point mutation – Polyploidy – Sequence databases – In vitro kinase assay


Zdroje

1. Jopling C, Sleep E, Raya M, Marti M, Raya A, Izpisua Belmonte JC. Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature. 2010;464: 606–9. doi: 10.1038/nature08899 20336145

2. Kikuchi K, Holdway JE, Werdich AA, Anderson RM, Fang Y, Egnaczyk GF, et al. Primary contribution to zebrafish heart regeneration by gata4(+) cardiomyocytes. Nature. 2010;464: 601–5. doi: 10.1038/nature08804 20336144

3. Oberpriller JO, Oberpriller JC. Response of the adult newt ventricle to injury. J Exp Zool. 1974;187: 249–53. doi: 10.1002/jez.1401870208 4813417

4. Robledo M. Myocardial regeneration in young rats. Am J Pathol. 1956;32: 1215–39. 13372753

5. Porrello ER, Mahmoud AI, Simpson E, Hill JA, Richardson JA, Olson EN, et al. Transient regenerative potential of the neonatal mouse heart. Science. 2011;331: 1078–80. doi: 10.1126/science.1200708 21350179

6. Zhu W, Zhang E, Zhao M, Chong Z, Fan C, Tang Y, et al. Regenerative Potential of Neonatal Porcine Hearts. Circulation. 2018;138: 2809–16. doi: 10.1161/CIRCULATIONAHA.118.034886 30030418

7. Ye L, D'Agostino G, Loo SJ, Wang CX, Su LP, Tan SH, et al. Early Regenerative Capacity in the Porcine Heart. Circulation. 2018;138: 2798–808. doi: 10.1161/CIRCULATIONAHA.117.031542 30030417

8. Westaby S, Archer N, Myerson SG. Cardiac development after salvage partial left ventriculectomy in an infant with anomalous left coronary artery from the pulmonary artery. J Thorac Cardiovasc Surg. 2008;136: 784–5. doi: 10.1016/j.jtcvs.2007.10.085 18805288

9. Haubner BJ, Schneider J, Schweigmann U, Schuetz T, Dichtl W, Velik-Salchner C, et al. Functional Recovery of a Human Neonatal Heart After Severe Myocardial Infarction. Circ Res. 2016;118: 216–21. doi: 10.1161/CIRCRESAHA.115.307017 26659640

10. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Executive Summary: Heart Disease and Stroke Statistics-2016 Update, A Report From the American Heart Association. Circulation. 2016;133: 447–54. doi: 10.1161/CIR.0000000000000366 26811276

11. Soonpaa MH, Kim KK, Pajak L, Franklin M, Field LJ. Cardiomyocyte DNA synthesis and binucleation during murine development. Am J Physiol. 1996;271: H2183–9. doi: 10.1152/ajpheart.1996.271.5.H2183 8945939

12. Li F, Wang X, Capasso JM, Gerdes AM. Rapid transition of cardiac myocytes from hyperplasia to hypertrophy during postnatal development. J Mol Cell Cardiol. 1996;28: 1737–46. doi: 10.1006/jmcc.1996.0163 8877783

13. Kellerman S, Moore JA, Zierhut W, Zimmer HG, Campbell J, Gerdes AM. Nuclear DNA content and nucleation patterns in rat cardiac myocytes from different models of cardiac hypertrophy. J Mol Cell Cardiol. 1992;24: 497–505. doi: 10.1016/0022-2828(92)91839-w 1386113

14. Brodsky WY, Arefyeva AM, Uryvaeva IV. Mitotic polyploidization of mouse heart myocytes during the first postnatal week. Cell Tissue Res. 1980;210: 133–44. doi: 10.1007/bf00232149 7407859

15. Xavier-Vidal R, Mandarim-de-Lacerda CA. Cardiomyocyte proliferation and hypertrophy in the human fetus: quantitative study of the myocyte nuclei. Bull Assoc Anat (Nancy). 1995;79: 27–31.

16. Mollova M, Bersell K, Walsh S, Savla J, Das LT, Park SY, et al. Cardiomyocyte proliferation contributes to heart growth in young humans. Proc Natl Acad Sci U S A. 2013;110: 1446–51. doi: 10.1073/pnas.1214608110 23302686

17. Laflamme MA, Murry CE. Heart regeneration. Nature. 2011;473: 326–35. doi: 10.1038/nature10147 21593865

18. Hesse M, Doengi M, Becker A, Kimura K, Voeltz N, Stein V, et al. Midbody Positioning and Distance Between Daughter Nuclei Enable Unequivocal Identification of Cardiomyocyte Cell Division in Mice. Circ Res. 2018;123: 1039–52. doi: 10.1161/CIRCRESAHA.118.312792 30355161

19. Leone M, Musa G, Engel FB. Cardiomyocyte binucleation is associated with aberrant mitotic microtubule distribution, mislocalization of RhoA and IQGAP3, as well as defective actomyosin ring anchorage and cleavage furrow ingression. Cardiovasc Res. 2018;114: 1115–31. doi: 10.1093/cvr/cvy056 29522098

20. Patterson M, Barske L, Van Handel B, Rau CD, Gan PH, Sharma A, et al. Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration. Nat Genet. 2017;49: 1346–53. doi: 10.1038/ng.3929 28783163

21. Gonzalez-Rosa JM, Sharpe M, Field D, Soonpa MH, Field LJ, Burns CE, et al. Myocardial Polyploidization creates a barrier to heart regeneration in zebrafish. Dev Cell. 2018;44: 433–46. doi: 10.1016/j.devcel.2018.01.021 29486195

22. Fan LL, Huang H, Jin JY, Li JJ, Chen YQ, Zhao SP, et al. Whole exome sequencing identifies a novel mutation (c.333+2T>C) of TNNI3K in a Chinese family with dilated cardiomyopathy and cardiac conduction disease. Gene. 2018;648: 63–7. doi: 10.1016/j.gene.2018.01.055 29355681

23. Xi Y, Honeywell C, Zhang D, Schwartzentruber J, Beaulieu CL, Tetreault M, et al. Whole exome sequencing identifies the TNNI3K gene as a cause of familial conduction system disease and congenital junctional ectopic tachycardia. Int J Cardiol. 2015;185: 114–6. doi: 10.1016/j.ijcard.2015.03.130 25791106

24. Theis JL, Zimmermann MT, Larsen BT, Rybakova IN, Long PA, Evans JM, et al. TNNI3K mutation in familial syndrome of conduction system disease, atrial tachyarrhythmia and dilated cardiomyopathy. Hum Mol Genet. 2014;23: 5793–804. doi: 10.1093/hmg/ddu297 24925317

25. Podliesna S, Delanne J, Miller L, Tester DJ, Uzunyan M, Yano S, et al. Supraventricular tachycardias, conduction disease, and cardiomyopathy in 3 families with the same rare variant in TNNI3K (p.Glu768Lys). Heart Rhythm. 2019;16: 98–105. doi: 10.1016/j.hrthm.2018.07.015 30010057

26. Lek M, Exome Aggregation Consortium. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536: 285–91. ExAC.broadinstitute.org. doi: 10.1038/nature19057 27535533

27. Wheeler FC, Tang H, Marks OA, Hadnott TN, Chu PL, Mao L, et al. Tnni3k modifies disease progression in murine models of cardiomyopathy. PLoS Genet. 2009;5: e1000647. doi: 10.1371/journal.pgen.1000647 19763165

28. Aberle H, Bauer A, Stappert J, Kispert A, Kemler R. beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J. 1997;16: 3797–804. doi: 10.1093/emboj/16.13.3797 9233789

29. Wang H, Chen C, Song X, Chen J, Zhen Y, Sun K, et al. Mef2c is an essential regulatory element required for unique expression of the cardiac-specific CARK gene. J Cell Mol Med. 2008;12: 304–15. doi: 10.1111/j.1582-4934.2007.00155.x 18021318

30. Patterson BD, Upham NS. A newly recognized family from the Horn of Africa, the Heterocephalidae (Rodentia: Ctenohystrica). Zool J Linnean Soc. 2014;172: 942–63.

31. Nei M, Xu P, Glazko G. Estimation of divergence times from multiprotein sequences for a few mammalian species and several distantly related organisms. Proc Natl Acad Sci U S A. 2001;98: 2497–502. doi: 10.1073/pnas.051611498 11226267

32. Fabre PH, Hautier L, Dimitrov D, Douzery EJ. A glimpse on the pattern of rodent diversification: a phylogenetic approach. BMC Evol Biol. 2012;12: 88. doi: 10.1186/1471-2148-12-88 22697210

33. Eigenbrod O, Debus KY, Reznick J, Bennett NC, Sanchez-Carranza O, Omerbasic D, et al. Rapid molecular evolution of pain insensitivity in multiple African rodents. Science. 2019;364: 852–9. doi: 10.1126/science.aau0236 31147513

34. Grimes KM, Voorhees A, Chiao YA, Han HC, Lindsey ML, Buffenstein R. Cardiac function of the naked mole-rat: ecophysiological responses to working underground. Am J Physiol Heart Circ Physiol. 2014;306: H730–7. doi: 10.1152/ajpheart.00831.2013 24363308

35. Grimes KM, Barefield DY, Kumar M, McNamara JW, Weintraub ST, de Tombe PP, et al. The naked mole-rat exhibits an unusual cardiac myofilament protein profile providing new insights into heart function of this naturally subterranean rodent. Pflugers Arch. 2017;469: 1603–13. doi: 10.1007/s00424-017-2046-3 28780592

36. Feng Y, Cao HQ, Liu Z, Ding JF, Meng XM. Identification of the dual specificity and the functional domains of the cardiac-specific protein kinase TNNI3K. Gen Physiol Biophys. 2007;26: 104–9. 17660584

37. Tang H, Xiao KH, Mao L, Rockman HA, Marchuk DA. Overexpression of TNNI3K, a cardiac-specific MAPKKK, promotes cardiac dysfunction. Journal of Molecular and Cellular Cardiology. 2013;54: 101–11. doi: 10.1016/j.yjmcc.2012.10.004 23085512

38. Rauch J, Volinsky N, Romano D, Kolch W. The secret life of kinases: functions beyond catalysis. Cell Commun Signal. 2011;9: 23. doi: 10.1186/1478-811X-9-23 22035226

39. Kurosaki T, Popp MW, Maquat LE. Quality and quantity control of gene expression by nonsense-mediated mRNA decay. Nat Rev Mol Cell Biol. 2019.

40. Puente BN, Kimura W, Muralidhar SA, Moon J, Amatruda JF, Phelps KL, et al. The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response. Cell. 2014;157: 565–79. doi: 10.1016/j.cell.2014.03.032 24766806

41. Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, et al. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science. 2005;308: 1909–11. doi: 10.1126/science.1106653 15879174

42. Huang TT, Naeemuddin M, Elchuri S, Yamaguchi M, Kozy HM, Carlson EJ, et al. Genetic modifiers of the phenotype of mice deficient in mitochondrial superoxide dismutase. Hum Mol Genet. 2006;15: 1187–94. doi: 10.1093/hmg/ddl034 16497723

43. Vagnozzi RJ, Gatto GJ Jr., Kallander LS, Hoffman NE, Mallilankaraman K, Ballard VL, et al. Inhibition of the cardiomyocyte-specific kinase TNNI3K limits oxidative stress, injury, and adverse remodeling in the ischemic heart. Sci Transl Med. 2013;5: 207ra141.

44. Lewis KN, Andziak B, Yang T, Buffenstein R. The naked mole-rat response to oxidative stress: just deal with it. Antioxid Redox Signal. 2013;19: 1388–99. doi: 10.1089/ars.2012.4911 23025341

45. Munro D, Baldy C, Pamenter ME, Treberg JR. The exceptional longevity of the naked mole-rat may be explained by mitochondrial antioxidant defenses. Aging Cell. 2019;18: e12916. doi: 10.1111/acel.12916 30768748

46. Hirose K, Payumo AY, Cutie S, Hoang A, Zhang H, Guyot R, et al. Evidence for hormonal control of heart regenerative capacity during endothermy acquisition. Science. 2019;364: 184–8. doi: 10.1126/science.aar2038 30846611

47. Buffenstein R, Woodley R, Thomadakis C, Daly TJ, Gray DA. Cold-induced changes in thyroid function in a poikilothermic mammal, the naked mole-rat. Am J Physiol Regul Integr Comp Physiol. 2001;280: R149–55. doi: 10.1152/ajpregu.2001.280.1.R149 11124146

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