Abstract
Considerable effort has gone into investigating mechanisms that underlie the developmental transition in which mammalian cardiomyocytes (CMs) switch from being able to proliferate during development, to essentially having lost that ability at maturity. This problem is interesting not only for scientific curiosity, but also for its clinical relevance because controlling the ability of mature CMs to replicate would provide a much-needed approach for restoring cardiac function in damaged hearts. In this review, we focus on the propensity of mature mammalian CMs to be multinucleated and polyploid, and the extent to which this may be necessary for normal physiology yet possibly disadvantageous in some circumstances. In this context, we explore whether the concept of the myonuclear domain (MND) in multinucleated skeletal muscle fibers might apply to cardiomyocytes, and whether cardio-MND size might be related to the transition of CMs to become multinuclear. Nuclei in CMs are almost certainly integrators of not only biochemical, but also—because of their central location within the myofibrils—mechanical information, and this multimodal, integrative function in adult CMs—involving molecules that have been extensively studied along with newly identified possibilities—could influence both gene expression as well as replication of the genome and the nuclei themselves.
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Notes
We have chosen to use “nuclearity” to refer to the number of nuclei in a cell, paralleling its definition in chemistry. Note that “nucleation” has been used more commonly in the cell biology literature to refer to the number of nuclei in a cell and also the process of increasing the number of nuclei in a cell, while it has different meanings in chemistry and biochemistry. In this review, we retain the limited use of “binucleation” to refer to the process of increasing the number of nuclei in a cell from one to two. Furthermore, to avoid confusion with the class of blood cells termed “mononuclear,” the commonly used, related terms “mononucleated” (instead of mononuclear), “binucleated,” “tetranucleated” and “multinucleated” are used to describe cells with one nucleus, two nuclei, four nuclei, or more than one nucleus, respectively.
References
Adler CP, Costabel U (1975) Cell number in human heart in atrophy, hypertrophy, and under the influence of cytostatics. Recent Adv Stud Cardiac Struct Metab 6:343–355
Ahuja P, Perriard E, Perriard JC, Ehler E (2004) Sequential myofibrillar breakdown accompanies mitotic division of mammalian cardiomyocytes. J Cell Sci 117:3295–3306. https://doi.org/10.1242/jcs.01159
Ahuja P, Perriard E, Pedrazzini T, Satoh S, Perriard JC, Ehler E (2007a) Re-expression of proteins involved in cytokinesis during cardiac hypertrophy. Exp Cell Res 313:1270–1283. https://doi.org/10.1016/j.yexcr.2007.01.009
Ahuja P, Sdek P, MacLellan WR (2007b) Cardiac myocyte cell cycle control in development, disease, and regeneration. Physiol Rev 87:521–544. https://doi.org/10.1152/physrev.00032.2006
Anatskaya OV, Vinogradov AE (2007) Genome multiplication as adaptation to tissue survival: evidence from gene expression in mammalian heart and liver. Genomics 89:70–80. https://doi.org/10.1016/j.ygeno.2006.08.014
Asumda FZ, Chase PB (2012) Nuclear cardiac troponin and tropomyosin are expressed early in cardiac differentiation of rat mesenchymal stem cells. Differentiation 83:106–115. https://doi.org/10.1016/j.diff.2011.10.002
Bae S, Xiao Y, Li G, Casiano CA, Zhang L (2003) Effect of maternal chronic hypoxic exposure during gestation on apoptosis in fetal rat heart. Am J Physiol Heart Circ Physiol 285:H983–H990. https://doi.org/10.1152/ajpheart.00005.2003
Benjamin EJ et al (2019) Heart disease and stroke statistics-2019 update: a report from the American Heart Association. Circulation 139:e56–e66. https://doi.org/10.1161/CIR.0000000000000659
Bensley JG, De Matteo R, Harding R, Black MJ (2016) Three-dimensional direct measurement of cardiomyocyte volume, nuclearity, and ploidy in thick histological sections. Sci Rep 6:23756. https://doi.org/10.1038/srep23756
Bergmann O et al (2009) Evidence for cardiomyocyte renewal in humans. Science 324:98–102. https://doi.org/10.1126/science.1164680
Bergmann O et al (2015) Dynamics of cell generation and turnover in the human heart. Cell 161:1566–1575. https://doi.org/10.1016/j.cell.2015.05.026
Bersell K, Arab S, Haring B, Kuhn B (2009) Neuregulin1/ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury. Cell 138:257–270. https://doi.org/10.1016/j.cell.2009.04.060
Botting KJ et al (2012) Early origins of heart disease: low birth weight and determinants of cardiomyocyte endowment. Clin Exp Pharmacol Physiol 39:814–823. https://doi.org/10.1111/j.1440-1681.2011.05649.x
Brayson D, Shanahan CM (2017) Current insights into LMNA cardiomyopathies: existing models and missing LINCs. Nucleus 8:17–33. https://doi.org/10.1080/19491034.2016.1260798
Broughton KM, Sussman MA (2017) Myocardial regeneration for humans- modifying biology and manipulating evolution. Circ J 81:142–148. https://doi.org/10.1253/circj.CJ-16-1228
Bugaisky L, Zak R (1979) Cellular growth of cardiac muscle after birth. Tex Rep Biol Med 39:123–138
Carvalho AB, de Carvalho AC (2010) Heart regeneration: past, present and future. World J Cardiol 2:107–111. https://doi.org/10.4330/wjc.v2.i5.107
Chase PB, Szczypinski MP, Soto EP (2013) Nuclear tropomyosin and troponin in striated muscle: new roles in a new locale? J Muscle Res Cell Motil 34:275–284. https://doi.org/10.1007/s10974-013-9356-7
Clubb FJ Jr, Bishop SP (1984) Formation of binucleated myocardial cells in the neonatal rat. An index for growth hypertrophy. Lab Invest 50:571–577
Cole LA, Dennis JH, Chase PB (2016) Commentary: epigenetic regulation of phosphodiesterases 2A and 3A underlies compromised b-adrenergic signaling in an iPSC model of dilated cardiomyopathy. Front Physiol 7:418. https://doi.org/10.3389/fphys.2016.00418
Collins MA et al (2017) Emery-Dreifuss muscular dystrophy-linked genes and centronuclear myopathy-linked genes regulate myonuclear movement by distinct mechanisms. Mol Biol Cell 28:2303–2317. https://doi.org/10.1091/mbc.E16-10-0721
de Lanerolle P, Serebryannyy L (2011) Nuclear actin and myosins: life without filaments. Nat Cell Biol 13:1282–1288. https://doi.org/10.1038/ncb2364
Duncan AW et al (2010) The ploidy conveyor of mature hepatocytes as a source of genetic variation. Nature 467:707–710. https://doi.org/10.1038/nature09414
Elhelaly WM, Lam NT, Hamza M, Xia S, Sadek HA (2016) Redox regulation of heart regeneration: an evolutionary tradeoff. Front Cell Dev Biol 4:137. https://doi.org/10.3389/fcell.2016.00137
Engel FB, Schebesta M, Keating MT (2006) Anillin localization defect in cardiomyocyte binucleation. J Mol Cell Cardiol 41:601–612. https://doi.org/10.1016/j.yjmcc.2006.06.012
Foglia MJ, Poss KD (2016) Building and re-building the heart by cardiomyocyte proliferation. Development 143:729–740. https://doi.org/10.1242/dev.132910
Folker ES, Ostlund C, Luxton GW, Worman HJ, Gundersen GG (2011) Lamin A variants that cause striated muscle disease are defective in anchoring transmembrane actin-associated nuclear lines for nuclear movement. Proc Natl Acad Sci USA 108:131–136. https://doi.org/10.1073/pnas.1000824108
Frawley LE, Orr-Weaver TL (2015) Polyploidy. Curr Biol 25:R353–R358. https://doi.org/10.1016/j.cub.2015.03.037
Garfinkel AC, Seidman JG, Seidman CE (2018) Genetic pathogenesis of hypertrophic and dilated cardiomyopathy. Heart Fail Clin 14:139–146. https://doi.org/10.1016/j.hfc.2017.12.004
Gonzalez-Martinez D et al (2018) Structural and functional impact of troponin C-mediated Ca2+ sensitization on myofilament lattice spacing and cross-bridge mechanics in mouse cardiac muscle. J Mol Cell Cardiol 123:26–37. https://doi.org/10.1016/j.yjmcc.2018.08.015
Gonzalez-Rosa JM, Sharpe M, Field D, Soonpaa MH, Field LJ, Burns CE, Burns CG (2018) Myocardial polyploidization creates a barrier to heart regeneration in Zebrafish. Dev Cell 44(433–446):e437. https://doi.org/10.1016/j.devcel.2018.01.021
Gude N, Muraski J, Rubio M, Kajstura J, Schaefer E, Anversa P, Sussman MA (2006) Akt promotes increased cardiomyocyte cycling and expansion of the cardiac progenitor cell population. Circ Res 99:381–388
Harvey W (1628) On the motion of the heart and blood in animals great minds series. Great minds series (classics in life sciences). Promethius Books, Amherst
Hassel C, Zhang B, Dixon M, Calvi BR (2014) Induction of endocycles represses apoptosis independently of differentiation and predisposes cells to genome instability. Development 141:112–123. https://doi.org/10.1242/dev.098871
Heineke J, Molkentin JD (2006) Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol 7:589–600. https://doi.org/10.1038/nrm1983
Hesse M, Doengi M, Becker A, Kimura K, Voeltz N, Stein V, Fleischmann BK (2018a) Midbody positioning and distance between daughter nuclei enable unequivocal identification of cardiomyocyte cell division in mice. Circ Res 123:1039–1052. https://doi.org/10.1161/CIRCRESAHA.118.312792
Hesse M, Welz A, Fleischmann BK (2018b) Heart regeneration and the cardiomyocyte cell cycle. Pflugers Arch 470:241–248. https://doi.org/10.1007/s00424-017-2061-4
Hofmann WA, Arduini A, Nicol SM, Camacho CJ, Lessard JL, Fuller-Pace FV, de Lanerolle P (2009) SUMOylation of nuclear actin. J Cell Biol 186:193–200. https://doi.org/10.1083/jcb.200905016
Johnston JR, Chase PB, Pinto JR (2018) Troponin through the looking-glass: emerging roles beyond regulation of striated muscle contraction. Oncotarget 9:1461–1482. https://doi.org/10.18632/oncotarget.22879
Jonker SS, Faber JJ, Anderson DF, Thornburg KL, Louey S, Giraud GD (2007) Sequential growth of fetal sheep cardiac myocytes in response to simultaneous arterial and venous hypertension. Am J Physiol Regul Integr Comp Physiol 292:R913–R919. https://doi.org/10.1152/ajpregu.00484.2006
Jopling C, Sleep E, Raya M, Marti M, Raya A, Izpisua Belmonte JC (2010) Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature 464:606–609. https://doi.org/10.1038/nature08899
Jopling C, Sune G, Faucherre A, Fabregat C, Izpisua Belmonte JC (2012) Hypoxia induces myocardial regeneration in zebrafish. Circulation 126:3017–3027. https://doi.org/10.1161/CIRCULATIONAHA.112.107888
Jungbluth H, Gautel M (2014) Pathogenic mechanisms in centronuclear myopathies. Front Aging Neurosci 6:339. https://doi.org/10.3389/fnagi.2014.00339
Kang MJ, Kim JS, Chae SW, Koh KN, Koh GY (1997) Cyclins and cyclin dependent kinases during cardiac development. Mol Cells 7:360–366
Keeling MC, Flores LR, Dodhy AH, Murray ER, Gavara N (2017) Actomyosin and vimentin cytoskeletal networks regulate nuclear shape, mechanics and chromatin organization. Sci Rep 7:5219. https://doi.org/10.1038/s41598-017-05467-x
Laflamme MA, Murry CE (2011) Heart regeneration. Nature 473:326–335. https://doi.org/10.1038/nature10147
Lee HO, Davidson JM, Duronio RJ (2009) Endoreplication: polyploidy with purpose. Genes Dev 23:2461–2477. https://doi.org/10.1101/gad.1829209
Leone M, Engel FB (2019) Advances in heart regeneration based on cardiomyocyte proliferation and regenerative potential of binucleated cardiomyocytes and polyploidization. Clin Sci (Lond) 133:1229–1253. https://doi.org/10.1042/CS20180560
Leone M, Musa G, Engel FB (2018) 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 114:1115–1131. https://doi.org/10.1093/cvr/cvy056
Li F, Wang X, Capasso JM, Gerdes AM (1996) Rapid transition of cardiac myocytes from hyperplasia to hypertrophy during postnatal development. J Mol Cell Cardiol 28:1737–1746. https://doi.org/10.1006/jmcc.1996.0163
Li F, McNelis MR, Lustig K, Gerdes AM (1997a) Hyperplasia and hypertrophy of chicken cardiac myocytes during posthatching development. Am J Physiol 273:R518–R526. https://doi.org/10.1152/ajpregu.1997.273.2.R518
Li F, Wang X, Gerdes AM (1997b) Formation of binucleated cardiac myocytes in rat heart: II Cytoskeletal organisation. J Mol Cell Cardiol 29:1553–1565. https://doi.org/10.1006/jmcc.1997.0403
Liu JX et al (2009) Myonuclear domain size and myosin isoform expression in muscle fibres from mammals representing a 100,000-fold difference in body size. Exp Physiol 94:117–129. https://doi.org/10.1113/expphysiol.2008.043877
Liu Z, Yue S, Chen X, Kubin T, Braun T (2010) Regulation of cardiomyocyte polyploidy and multinucleation by CyclinG1. Circ Res 106:1498–1506. https://doi.org/10.1161/CIRCRESAHA.109.211888
Margall-Ducos G, Celton-Morizur S, Couton D, Bregerie O, Desdouets C (2007) Liver tetraploidization is controlled by a new process of incomplete cytokinesis. J Cell Sci 120:3633–3639. https://doi.org/10.1242/jcs.016907
Maron BJ, Maron MS (2013) Hypertrophic cardiomyopathy. Lancet 381:242–255. https://doi.org/10.1016/S0140-6736(12)60397-3
Marques MdA, de Oliveira GAP (2016) Cardiac troponin and tropomyosin: structural and cellular perspectives to unveil the hypertrophic cardiomyopathy phenotype. Front Physiol 7:429. https://doi.org/10.3389/fphys.2016.00429
Martins AS et al (2015) In vivo analysis of troponin C Knock-In (A8 V) mice: evidence that TNNC1 is a hypertrophic cardiomyopathy susceptibility gene. Circ Cardiovasc Genet 8:653–664. https://doi.org/10.1161/CIRCGENETICS.114.000957
Matrone G, Tucker CS, Denvir MA (2017) Cardiomyocyte proliferation in zebrafish and mammals: lessons for human disease. Cell Mol Life Sci 74:1367–1378. https://doi.org/10.1007/s00018-016-2404-x
Mazzotti AL, Coletti D (2016) The need for a consensus on the locution “Central Nuclei” in striated muscle myopathies. Front Physiol 7:577. https://doi.org/10.3389/fphys.2016.00577
Meckert PC, Rivello HG, Vigliano C, Gonzalez P, Favaloro R, Laguens R (2005) Endomitosis and polyploidization of myocardial cells in the periphery of human acute myocardial infarction. Cardiovasc Res 67:116–123. https://doi.org/10.1016/j.cardiores.2005.02.017
Mercola M, Ruiz-Lozano P, Schneider MD (2011) Cardiac muscle regeneration: lessons from development. Genes Dev 25:299–309. https://doi.org/10.1101/gad.2018411
Miko M, Kyselovic J, Danisovic I, Barczi T, Polak S, Varga I (2017) Two nuclei inside a single cardiac muscle cell. More questions than answers about the binucleation of cardiomyocytes. Biologia. https://doi.org/10.1515/biolog-2017-0107
Mohamed TMA et al (2018) Regulation of cell cycle to stimulate adult cardiomyocyte proliferation and cardiac regeneration. Cell 173(104–116):e112. https://doi.org/10.1016/j.cell.2018.02.014
Murach KA, Englund DA, Dupont-Versteegden EE, McCarthy JJ, Peterson CA (2018) Myonuclear domain flexibility challenges rigid assumptions on satellite cell contribution to skeletal muscle fiber hypertrophy. Front Physiol 9:635. https://doi.org/10.3389/fphys.2018.00635
Nunez Lopez YO, Messi ML, Pratley RE, Zhang T, Delbono O (2018) Troponin T3 associates with DNA consensus sequence that overlaps with p53 binding motifs. Exp Gerontol 108:35–40. https://doi.org/10.1016/j.exger.2018.03.012
Oparil S, Bishop SP, Clubb FJ Jr (1984) Myocardial cell hypertrophy or hyperplasia. Hypertension 6:III38–III43
Orr-Weaver TL (2015) When bigger is better: the role of polyploidy in organogenesis. Trends Genet 31:307–315. https://doi.org/10.1016/j.tig.2015.03.011
Pannérec A, Marazzi G, Sassoon D (2012) Stem cells in the hood: the skeletal muscle niche. Trends Mol Med 18:599–606. https://doi.org/10.1016/j.molmed.2012.07.004
Paradis AN, Gay MS, Zhang L (2014) Binucleation of cardiomyocytes: the transition from a proliferative to a terminally differentiated state. Drug Discov Today 19:602–609. https://doi.org/10.1016/j.drudis.2013.10.019
Parvatiyar MS, Pinto JR, Dweck D, Potter JD (2010) Cardiac troponin mutations and restrictive cardiomyopathy. J Biomed Biotechnol 2010:350706. https://doi.org/10.1155/2010/350706
Patterson M et al (2017) Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration. Nat Genet 49:1346–1353. https://doi.org/10.1038/ng.3929
Pavlath GK, Rich K, Webster SG, Blau HM (1989) Localization of muscle gene products in nuclear domains. Nature 337:570–573. https://doi.org/10.1038/337570a0
Pinto JR, Muller-Delp J, Chase PB (2017) Will you still need me (Ca2+, TnT and DHPR), will you still cleave me (calpain), when I’m 64? Aging Cell 16:202–204. https://doi.org/10.1111/acel.12560
Poolman RA, Gilchrist R, Brooks G (1998) Cell cycle profiles and expressions of p21CIP1 AND P27KIP1 during myocyte development. Int J Cardiol 67:133–142
Porrello ER, Mahmoud AI, Simpson E, Hill JA, Richardson JA, Olson EN, Sadek HA (2011) Transient regenerative potential of the neonatal mouse heart. Science 331:1078–1080. https://doi.org/10.1126/science.1200708
Resende RR, Andrade LM, Oliveira AG, Guimarães ES, Guatimosim S, Leite MF (2013) Nucleoplasmic calcium signaling and cell proliferation: calcium signaling in the nucleus. Cell Commun Signal 11:14. https://doi.org/10.1186/1478-811X-11-14
Rumyantsev PP (1977) Interrelations of the proliferation and differentiation processes during cardiact myogenesis and regeneration. Int Rev Cytol 51:186–273
Rumyantsev PP (1991) Growth and hyperplasia of cardiac muscle cells. Harwood Academic Publishers, Reading
Semsarian C, Ingles J, Maron MS, Maron BJ (2015) New perspectives on the prevalence of hypertrophic cardiomyopathy. J Am Coll Cardiol 65:1249–1254. https://doi.org/10.1016/j.jacc.2015.01.019
Senyo SE et al (2013) Mammalian heart renewal by pre-existing cardiomyocytes. Nature 493:433–436. https://doi.org/10.1038/nature11682
Serebryannyy LA, Yuen M, Parilla M, Cooper ST, de Lanerolle P (2016) The effects of disease models of nuclear actin polymerization on the nucleus. Front Physiol 7:454. https://doi.org/10.3389/fphys.2016.00454
Shin AN, Han L, Dasgupta C, Huang L, Yang S, Zhang L (2018) SIRT1 increases cardiomyocyte binucleation in the heart development. Oncotarget 9:7996–8010. https://doi.org/10.18632/oncotarget.23847
Soonpaa MH, Field LJ (1997) Assessment of cardiomyocyte DNA synthesis in normal and injured adult mouse hearts. Am J Physiol 272:H220–H226. https://doi.org/10.1152/ajpheart.1997.272.1.H220
Soonpaa MH, Field LJ (1998) Survey of studies examining mammalian cardiomyocyte DNA synthesis. Circ Res 83:15–26
Soonpaa MH, Kim KK, Pajak L, Franklin M, Field LJ (1996) Cardiomyocyte DNA synthesis and binucleation during murine development. Am J Physiol 271:H2183–H2189. https://doi.org/10.1152/ajpheart.1996.271.5.H2183
Sundaresan NR, Pillai VB, Gupta MP (2011) Emerging roles of SIRT1 deacetylase in regulating cardiomyocyte survival and hypertrophy. J Mol Cell Cardiol 51:614–618. https://doi.org/10.1016/j.yjmcc.2011.01.008
Tane S, Ikenishi A, Okayama H, Iwamoto N, Nakayama KI, Takeuchi T (2014) CDK inhibitors, p21(Cip1) and p27(Kip1), participate in cell cycle exit of mammalian cardiomyocytes. Biochem Biophys Res Commun 443:1105–1109. https://doi.org/10.1016/j.bbrc.2013.12.109
Teixeira CE, Duarte JA (2011) Myonuclear domain in skeletal muscle fibers. A critical review. Arch Exerc Health Dis 2:92–101
Tong W, Xiong F, Li Y, Zhang L (2013) Hypoxia inhibits cardiomyocyte proliferation in fetal rat hearts via upregulating TIMP-4. Am J Physiol Regul Integr Comp Physiol 304:R613–R620. https://doi.org/10.1152/ajpregu.00515.2012
Tormos AM, Talens-Visconti R, Sastre J (2015) Regulation of cytokinesis and its clinical significance. Crit Rev Clin Lab Sci 52:159–167. https://doi.org/10.3109/10408363.2015.1012191
van Amerongen MJ, Engel FB (2008) Features of cardiomyocyte proliferation and its potential for cardiac regeneration. J Cell Mol Med 12:2233–2244. https://doi.org/10.1111/j.1582-4934.2008.00439.x
Virag JI, Murry CE (2003) Myofibroblast and endothelial cell proliferation during murine myocardial infarct repair. Am J Pathol 163:2433–2440. https://doi.org/10.1016/S0002-9440(10)63598-5
Vivien CJ, Hudson JE, Porrello ER (2016) Evolution, comparative biology and ontogeny of vertebrate heart regeneration. NPJ Regen Med 1:16012. https://doi.org/10.1038/npjregenmed.2016.12
Walsh S, Ponten A, Fleischmann BK, Jovinge S (2010) Cardiomyocyte cell cycle control and growth estimation in vivo–an analysis based on cardiomyocyte nuclei. Cardiovasc Res 86:365–373. https://doi.org/10.1093/cvr/cvq005
Willott RH, Gomes AV, Chang AN, Parvatiyar MS, Pinto JR, Potter JD (2010) Mutations in Troponin that cause HCM, DCM AND RCM: what can we learn about thin filament function? J Mol Cell Cardiol 48:882–892. https://doi.org/10.1016/j.yjmcc.2009.10.031
Wills AA, Holdway JE, Major RJ, Poss KD (2008) Regulated addition of new myocardial and epicardial cells fosters homeostatic cardiac growth and maintenance in adult zebrafish. Development 135:183–192. https://doi.org/10.1242/dev.010363
Wu X, Bers DM (2006) Sarcoplasmic reticulum and nuclear envelope are one highly interconnected Ca2+ store throughout cardiac myocyte. Circ Res 99:283–291. https://doi.org/10.1161/01.RES.0000233386.02708.72
Wu H et al (2015) Epigenetic regulation of phosphodiesterases 2A and 3A underlies compromised b-adrenergic signaling in an iPSC model of dilated cardiomyopathy. Cell Stem Cell 17:89–100. https://doi.org/10.1016/j.stem.2015.04.020
Xu Z et al (2017) Cardiac troponin T and fast skeletal muscle denervation in ageing. J Cachexia Sarcopenia Muscle 8:808–823. https://doi.org/10.1002/jcsm.12204
Yablonka-Reuveni Z (2011) The skeletal muscle satellite cell: still young and fascinating at 50. J Histochem Cytochem 59:1041–1059. https://doi.org/10.1369/0022155411426780
Yotti R, Seidman CE, Seidman JG (2019) Advances in the genetic basis and pathogenesis of sarcomere cardiomyopathies. Annu Rev Genom Hum Genet. https://doi.org/10.1146/annurev-genom-083118-015306
Zebrowski DC, Engel FB (2013) The cardiomyocyte cell cycle in hypertrophy, tissue homeostasis, and regeneration. Rev Physiol Biochem Pharmacol 165:67–96. https://doi.org/10.1007/112_2013_12
Zhang T et al (2016) Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1, and enhances skeletal muscle force in aging sedentary mice. Aging Cell 15:488–498. https://doi.org/10.1111/acel.12453
Zhang S et al (2018) The polyploid state plays a tumor-suppressive role in the liver. Dev Cell 44(447–459):e445. https://doi.org/10.1016/j.devcel.2018.01.010
Zhurinsky J, Leonhard K, Watt S, Marguerat S, Bahler J, Nurse P (2010) A coordinated global control over cellular transcription. Curr Biol 20:2010–2015. https://doi.org/10.1016/j.cub.2010.10.002
Zimmet J, Ravid K (2000) Polyploidy: occurrence in nature, mechanisms, and significance for the megakaryocyte-platelet system. Exp Hematol 28:3–16
Acknowledgements
We thank: Mark Bauer in Florida State University’s College of Medicine for assistance with artistic development and graphic design of Fig. 1; Karissa Dieseldorff Jones and Jennifer M. Le Patourel for expert assistance with obtaining and imaging isolated cardiomyocytes (Fig. 2) using the microscopy facilities of Florida State University’s Biological Science Imaging Resource in the Department of Biological Science; Drs. Jonathan Bensley and M. Jane Black for permission to plot in Fig. 3 their original data from Table 1 in Bensley et al. (2016) that was published under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0); and Dr. Jerome Irianto, Jamie R. Johnston, Karissa Dieseldorff Jones and Jennifer M. Le Patourel for helpful discussions. Supported by U.S. National Institutes of Health National Heart, Lung and Blood Institute Grant No. R01 HL128683 to JRP.
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Landim-Vieira, M., Schipper, J.M., Pinto, J.R. et al. Cardiomyocyte nuclearity and ploidy: when is double trouble?. J Muscle Res Cell Motil 41, 329–340 (2020). https://doi.org/10.1007/s10974-019-09545-7
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DOI: https://doi.org/10.1007/s10974-019-09545-7