CoChat
Sign Up
Cited by 199Genomics and Chromatin DynamicsCardiomyopathy and Myosin StudiesCardiac electrophysiology and arrhythmias

Regulation of myosin heavy chain genes in the heart.

Open access
Morkin, E·1993·Circulation
DOI 10.1161/01.cir.87.5.1451
Open this paper in CoChat — free accountOpen PDF

Abstract

Advances in our knowledge of the regulation of cardiac myosin isoforms made possible by molecular cloning of the alpha- and beta-MHCs genes are reviewed. Expression of these genes in heart does not seem to require MyoD or related proteins of the skeletal muscle myogenic program. Cardiac MHC genes are under the control of T3, which stimulates transcription of the alpha-MHC gene and inhibits beta-MHC mRNA production both in vivo and in cultured heart cells. The responsiveness of the genes to T3 varies in different mammals, however. The genes are most responsive in rat and rabbit, intermediate in sensitivity in calf and subhuman primate (baboon), and very resistant in the dog. The human alpha-MHC gene is T3-inducible in ventricle, but the degree of response has not been quantified. Introduction of chimeric plasmids containing 5' flanking sequences of cardiac MHC genes fused to the CAT gene into cultured heart cells and transgenic animals has permitted identification of regulatory elements. Although the genes are closely linked in genomic DNA, they are controlled independently. The element within the alpha-MHC promoter responsible for induction by T3 is located approximately 160 base pairs from the transcription initiation site. Additional transcriptional activators located 5' upstream amplify the response to T3, probably by looping out intervening DNA sequences. The proximal region of the beta-MHC gene contains important regulatory elements, including those required for repression by T3, muscle-specific expression, a MyoD-independent positive element, and a hormone-independent repressor.(ABSTRACT TRUNCATED AT 250 WORDS)

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1161/01.cir.87.5.1451

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In animal models, T3 has a positive direct inotropic effect.

    “In animal models T 3 has a positive direct inotropic effect by inducing a predominant synthesis of fast ␣-isoforms of heavy myosin chains and by increasing calcium-adenosine triphosphatase and cAMP levels, together with the number and sensitivity of ␤-adrenergic receptors (6 -10).”

    From The Role of Thyroid Hormone in Blood Pressure Homeostasis: Evidence from Short-Term Hypothyroidism in Humans (2002) · cites this paper as [7]

    In Regulatory Factors (page not provided), the paper describes an inotropic action of thyroid hormone, T3 stimulation of calcium uptake, and thyroid-hormone-induced fast myosin isoforms in rabbits and rats. It also says an isoform switch is unlikely to be the major mechanism of that inotropic action. The cited passages do not establish the claimed increases in cAMP or in the number and sensitivity of β-adrenergic receptors. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 72 · Cited by 199

Research works printed but not linked: 83

  1. Eisenberg E, Green LE: The relation of muscle biochemistry to muscle physiology. Annu Rev Physiol 1980;42:293-309
  2. Morkin E, Flink IL, Goldman S: Biochemical and physiologic effects of thyroid hormone on cardiac performance. Prog Cardio- vasc Dis 1983;25:435-464
  3. Hoh JFY, McGrath PA, Hale PT: Electrophoretic analysis of multiple forms of rat cardiac myosin: Effects of hypophysectomy and thyroid replacement. J Mol Cell Cardiol 1978;10:1053-1076
  4. Matsuoka R. Beisel KW, Furutani M, Arai S. Takao A: Complete sequence of human cardiac a-myosin heavy chain gene and amino acid comparison to other myosins based on structural and func- tional differences. Am J Med Genet 1991;41:537-547
  5. Jaenicke T, Diederich KW, Hass W, Schleich J, Lichter P, Pfordt M, Bach A, Vosberg H-P: The complete sequence of the human f-myosin gene and a comparative analysis of its product. Genomics 1990;8:194-206
  6. Liew C-C, Sole MJ, Yamauchi-Takihara K, Kellam B, Anderson DH, Lin L, Liew JC: Complete sequence and organization of the human cardiac /8-myosin heavy chain gene. Nucleic Acids Res 1990; 18:3647-3651
  7. McNally EM, Kraft R, Bravo-Zehnder M, Taylor DA, Leinwand LA: Full-length rat alpha and beta cardiac myosin heavy chain sequences: Comparisons suggest a molecular basis for function differences. J Mol Biol 1989;210:665-671
  8. Gustafson TA, Markham BE, Bahl JJ, Morkin E: Thyroid hormone regulates the expression of a transfected a-myosin heavy chain gene in fetal heart cells. Proc Natl Acad Sci U S A 1987;84: 3122-3126
  9. Watkins H, Rosenweig A, Hwang D-S, Levi T, McKenna W, Seid- man CE, Seidman JG: Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomy- opathy. N Engl J Med 1992;326:1108-1114
  10. Tanigawa G, Jarcho JA, Kass S, McKenna W, Seidman CE, Seid- man JG: A molecular basis for familial hypertrophic cardiomyop- athy: An alpha/beta myosin heavy chain fusion gene. Cell 1990;62: 991-998
  11. Swynghedauw B: Developmental and functional adaptions of con- tractile proteins in cardiac and skeletal muscles. Physiol Rev 1986; 66:710-771
  12. Saez IU, Gianola KM, McNally EM, Feghali R, Eddy R, Shows TB, Leinwand LA: Human cardiac myosin heavy chain genes and their linkage in the genome. Nucleic Acids Res 1987;15:5443-5459
  13. Mahdavi V, Strehler EE, Periasamy M, Wieczorek DF, Izumo S, Nadal-Ginard B: Cardiac myosin heavy chain genes are organized in tandem. Proc Natl Acad Sci U S A 1984;81:2626-2630
  14. Lyons GE, Schiaffino S, Sasson D, Barton P, Buckingham M: Developmental regulation of myosin gene expression in mouse cardiac muscle. Cell Biol 1990;111:2427-2436
  15. Sassoon DA, Gamer I, Buckingham M: Transcripts of a-cardiac and a-skeletal actins are early markers for myogenesis in the mouse embryo. Development 1988;104:55-164
  16. Lompre AM, Nadal-Ginard B, Mahdavi V: Expression of the car- diac ventricular alpha-and beta-myosin heavy chain genes is devel- opmentally and hormonally regulated. J Biol Chem 1984;259: 6437-6446
  17. Kubabayashi M, Tsuchimochi H, Komuro I, Takaku F, Yazaki Y: Molecular cloning and characterization of human a-and f-myosin heavy chain cDNA clones: Regulation of expression during devel- opment and pressure overload in human atrium. J Clin Invest 1988;82:524-531
  18. Everett AW: Isomyosin expression in human heart in early pre- and post-natal life. J Mol Cell Cardiol 1986;18:607-615
  19. Tapscott SJ, Weintraub H: MyoD and the regulation of myogenesis by helix-loop-helix proteins. J Clin Invest 1991;87:1113-1138
  20. Miner JH, Miller JB, Wold BJ: Skeletal muscle phenotypes initi- ated by ectopic MyoD in transgenic mouse heart. Development 1992;114:853-860
  21. Gupta MP, Gupta M, Zak R, Sukhatme VP: Egr-1, a serum- inducible zinc finger protein, regulates transcription of the rat cardiac a-myosin heavy chain gene. J Biol Chem 1991;266: 12813-12816
  22. Boheler KR, Chassagne C, Martin X, Wisnewsky C, Schwartz K: Cardiac expressions of a-and /3-myosin heavy chains and sarco- meric a-actins are regulated through transcriptional mechanisms. J Biol Chem 1992;267:12979-12985
  23. Izumo S, Lompre AM, Matsuoka R, Koren G, Schwartz K: Myosin heavy chain messenger RNA and protein isoform transitions dur- ing cardiac hypertrophy: Interaction between hemodynamic and thyroid hormone-induced signals. J Clin Invest 1988;79:970-977
  24. Imamura S-I, Matsuoka R, Hiratsuka E, Kimura M, Nakanishi T, Nishikawa T, Furutani Y, Takao A: Adaptational changes of MHC gene expression and isozyme transition in cardiac overloading. Am J Physiol 1991(Heart Circ Physiol 29);260:H73-H79
  25. Gay RG, Graham S, Aquirre M, Goldman S, Morkin E: Effects of 10- to 12-day treatment with L-thyroxlne in rats with myocardial infarc- tion. Am J Physiol 1988(Heart Circ Physiol 24);255:H801-H806
  26. Schaible TF, Malhotra A, Ciambrone G, Scheuer J: The effects of gonadectomy on left ventricular function and cardiac contractile proteins in male and female rats. Circ Res 1984;54:38-49
  27. Dillman WH: Influence of thyroid hormone administration on myosin ATPase activity and myosin isoenzyme distribution in the heart of diabetic rats. Metabolism 1982;31:199-204
  28. Effron MB, Bhatnager GM, Spurgeon HA, Arroyo R, Lakatta EG: Changes in myosin isoenzymes, ATPase activity, and contraction during in rat cardiac muscle with aging can be modulated by thyroxine. Circ Res 1987;60:238-245
  29. Rupp H, Wahl R: Influence of thyroid hormones and catechol- amines on myosin of swim-exercised rats. J Appl Physiol 1990;68: 973-978
  30. Sheer D, Morkin E: Myosin isoenzyme expression in rat ventricle: Effects of thyroid hormone analogs, catecholamines, glucocorti- coids and high carbohydrate diet. J Pharmacol Exp Ther 1984;229: 872-879
  31. Wang DL, Chen JJ, Shin NL, Kao YC, Hsu KH, Huang WY, Liew C-C: Endothelin stimulates cardiac a-and P-myosin heavy chain gene expression. Biochem Biophys Res Commun 1992;183: 1260-1265
  32. Nagai R, Pritzi N, Low RB, Stirewalt WS, Zak R, Alpert NR, Litten RZ: Myosin isozyme synthesis and mRNA levels in pres- sure-overloaded rabbit hearts. Circ Res 1987;60:692-699
  33. Sinha AM, Umeda PK, Kavinsky CJ, Rajamanicksm C, Hsu H-J, Jakovcic S, Rabinowitz M: Molecular cloning of mRNA sequence for cardiac a-and 3-form myosin heavy chains: Expression in ventricles of normal, hypothyroid, and thyrotoxic rabbits. Proc Natl Acad Sci U S A 1982;79:5847-5851
  34. Nag AC, Chen M: Expression of myosin isoforms in cardiac muscle cells in culture. Biochem J 1984;221:21-26
  35. Gustafson TA, Bahl JJ, Markham BE, Roeske WR, Morkin E: Hormonal regulation of myosin heavy chain and a-actin gene expression in cultured fetal rat heart myocytes. J Biol Chem 1987; 262:13316-13322
  36. Waspe LE, Ordahl CP, Simpson PC: The cardiac ,-myosin heavy chain gene is selectively induced in a1-adrenergic receptor-stimulated hypertrophy of cultured rat heart myocytes. J Clin Invest 1990;85: 1206-1214
  37. Gupta MP, Gupta M, Stewart A, Zak R: Activation of alpha- myosin heavy chain gene expression by cAMP in cultured fetal rat heart myocytes. Biochem Biophys Res Commun 1991;174:1196-1203
  38. Bouvagnet P, Leger J, Pons F, Deschesne C, Leger JJ: Fiber types and myosin types in human atrial and ventricular myocardium: An anatomical description. Circ Res 1984;55:794-804
  39. Gorza L, Mercadier JJ, Schwartz K, Thornell LE, Sartore S, Schi- affino S: Myosin types in the human heart: An immunofluores- cence study of normal and hypertrophied atrial and ventricular myocardium. Circ Res 1984;54:694-702
  40. Ladenson PW, Sherman SI, Baughman KL, Ray PE, Feldman AM: Reversible alterations in myocardial gene expression in a young man with dilated cardiomyopathy. Proc NatlAcad Sci U SA 1992; 89:5251-5255
  41. Goldman S, Olajos M, Friedman H, Roeske WR, Morkin E: Left ventricular performance in conscious thyrotoxic calves. Am J Phys- iol 1982(Heart Circ Physiol 11);242:H113-H121
  42. Taylor RG, Covell JW, Ross J Jr: Influence of the thyroid state on left ventricular tension-velocity relationship in the intact, sedated dog. J Clin Invest 1969;48:775-784
  43. Dillman WH: Biochemical basis of thyroid hormone action in the heart. Am J Med 1990;88:626-630
  44. Ptashne M: How eukaryotic transcriptional activators work. Nature 1988;335:683-689
  45. Jones NC, Rigby PWJ, Ziff EB: Trans-acting protein factors and the regulation of eukaryotic transcription: Lessons from studies on DNA tumor viruses. Genes Dev 1988;2:267-281
  46. Tsika RW, Bahl JJ, Leinwand LA, Morkin E: Thyroid hormone regulates expression of a transfected human a-myosin heavy chain gene in fetal rat heart cells. Proc NatlAcad Sci USA 1990;87:379-383
  47. Evans RM: Steroid and thyroid hormone receptors as transcriptional regulators of development and physiology. Science 1988;240:889-895
  48. O'Mally BW: The steroid receptor superfamily: More excitement predicted for the future. Mol Endocrinol 1990;4:363-369
  49. Izumo S, Mahdavi V: Thyroid hormone receptor alpha isoforms generated by alternative splicing differentially activate myosin HC gene transcription. Nature 1988;334:539-542
  50. Glass CK, Holloway JM, Devary OV, Rosenfeld MG: The thyroid hormone receptor binds with opposite transcriptional effects to a common sequence motif in thyroid hormone and estrogen response elements. Cell 1988;54:313-323
  51. Flink IL, Morkin E: Interaction of thyroid hormone receptors with strong and weak cis-acting elements in the human a-myosin heavy chain gene promoter. J Biol Chem 1990;265:11233-11237
  52. Koenig J, Brent GA, Warne RL, Larsen PR, Moore DD: Thyroid hormone receptor binds to a site in the rat growth hormone pro- moter required for induction by thyroid hormone. Proc Natl Acad Sci U S A 1987;84:5670-5674
  53. Umesono K, Murakami KK, Thompson CC, Evans RM: Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and vitamin D3 receptors. Cell 1991;65:1255-1266
  54. Yu VC, Delert C, Andersen B, Holloway JM, Devary OV, Naar AM, Kim SY, Boutin J-M, Glass CK, Rosenfeld MG: RXRfl: A coregulator that enhances binding of retinoic acid, thyroid hor- mone, and vitamin D receptors to their cognate response elements. Cell 1991;67:1251-1266
  55. Markham BE, Bahl JJ, Gustafson TA, Morkin E: Interaction of a protein factor within a thyroid hormone-sensitive region of rat a-myosin heavy chain gene. J Biol Chem 1987;262:12856-12862
  56. Mably JD, Sole MJ, Liew C-C: Characterization of the GArC Motif: A novel cis-acting element of the human myosin heavy chain genes. J Biol Chem 1993;268:476-482
  57. Morkin E, Bahl JJ, Markham BE: Control of myosin heavy chain gene expression by thyroid hormone, in Kedes LH, Stockdale FE (eds): Cellular and Molecular Biology of Muscle Development, UCLA Symposia on Molecular and Cellular Biology, New Series, vol 93. New York, Alan R Liss, 1989, pp 381-389
  58. Acsadi G, Jiao S, Duke D, Williams P, Chog W, Wolff JA: Direct gene transfer and expression into rat heart in vivo. New Biologist 1991;3:71-81
  59. Buttrick PM, Kass A, Kitsis RN, Kaplan ML, Leinwand LA: Behavior of genes directly injected into the rat heart in vivo. Circ Res 1992;70:193-198
  60. Kitsis RN, Buttrick PM, McNally EM, Kaplan ML, Leinwand LA: Hormonal modulation of a gene injected into rat heart in vivo. Proc Natl Acad Sci U S A 1991;88:4138-4142
  61. Ojamaa K, Klein I: Thyroid hormone regulation of alpha-myosin heavy chain promoter activity assessed by in vivo DNA transfer in rat heart. Biochem Biophys Res Commun 1991;179:1269-1275
  62. Subramaniam A, Jones WK, Gulick J, Wert S, Neumann J, Rob- bins J: Tissue-specific regulation of the a-myosin heavy chain gene promoter in transgenic mice. J Biol Chem 1991;266:24613-24620
  63. Subramaniam A, Gulick A, Neumann J, Knotts S, Robbins J: Transgenic analysis of the thyroid response elements in the a-car- diac myosin heavy chain gene promoter. J Bio Chem 1993;268: 66. Flink IL, Edwards JG, Bahl JJ, Liew C-C, Sole M, Morkin E: Characterization of a strong positive cis-acting element of the human 8-myosin heavy chain gene in fetal rat heart cells. J Biol Chem 1992;267:9917-9924
  64. Mar JH, Ordahl CP: M-CAT binding factor, a novel trans-acting factor governing muscle-specific transcription. Mol Cell Biol 1990; 10:4271-4283
  65. Parmacek MS, Anuradha JV, Shen T, Barr E, Jung F, Leiden JM: Identification and characterization of a cardiac-specific transcrip- tional regulatory element in the slow/cardiac troponin C gene. Mol Cell Biol 1992;12:1967-1976
  66. Xiao JH, Davidson I, Matthes H, Garnier J-M, Chambon P: Clon- ing, expression, and transcriptional properties of the human enhancer factor TEF-1. Cell 1991;65:551-568
  67. Farrance IKG, Mar JH, Ordahl CP: M-CAT binding factor is related to the SV 40 enhancer binding factor, transcription enhancer factor 1. J Biol Chem 1992;267:17234-17240
  68. Hu Y-F, Luscher B, Admon A, Mermod N, Tjian R: Transcription factor AP-4 contains multiple dimerization domains that regulate dimer specificity. Genes Dev 1990;4:1741-1752
  69. Nelson C, Shen L-P, Meister A, Fodor E, Rutter WJ: Pan: A transcriptional regulator that binds chymotrypsin, insulin, and AP-4 enhancer motifs. Genes Dev 1990;4:1035-1043
  70. Rosenthal N, Kornhauser JM, Donoghue M, Rosen KM, Merlie JP: Myosin light chain enhancer activates muscle-specific, devel- opmentally regulated gene expression in transgenic mice. Proc Natl Acad Sci U S A 1989;86:7780-7784
  71. Jaynes JJ, Chamberlain J, Bushkin J, Johnson J, Hauschka S: Transcriptional regulation of the muscle creatine kinase gene and regulated expression in transfected mouse myoblasts. Mol Cell Biol 1986;6:2855-2864
  72. Thompson WR, Nadal-Ginard B, Mahdavi VL: A MyoDi- independent muscle-specific enhancer controls expression of the 3-myosin heavy chain in skeletal and cardiac muscle cells. J Biol Chem 1991;266:22678-22688
  73. Shimizu N, Prior G, Umeda PK, Zak R: Cis-acting elements responsible for muscle-specific expression of the myosin heavy chain gene. Nucleic Acids Res 1992;20:1793-1799
  74. Yu Y-T, Nadal-Ginard B: Interaction of nuclear proteins with a positive cis-acting element of rat embryonic myosin heavy chain promoter. Mol Cell Biol 1989;9:1839-1849
  75. Edwards JG, Bahl JJ, Flink I, Milavetz J, Goldman S, Morkin E: A repressor region in the human 3-myosin heavy chain gene that has partial position dependency. Biochem Biophys Res Commun 1992; 189:504-510
  76. Rajavashisth TB, Taylor AK, Andalibi A, Svenson KL, Lusis AJ: Identification of a zinc-finger protein that binds to the sterol reg- ulatory element. Science 1989;245:640-643
  77. Chatteree V, Lee J-K, Rentoumis A, Jameson JL: Negative reg- ulation of the thyroid stimulating hormone a gene by thyroid hormone: Receptor interaction adjacent to the TATA box. Proc Natl Acad Sci USA 1989;86:9114-9118
  78. Crone DE, Kim H-S, Spindler SR: a And p8 thyroid hormone receptors bind immediately adjacent to the rat growth hormone gene TATA in a negatively hormone-responsive region. J Biol Chem 1990;265:10851-10856
  79. Baniahmad A, Steiner C, Kohne K, Renkawitz R: Modular struc- ture of a chicken lysozyme silencer: Involvement of an unusual thyroid hormone receptor. Cell 1990;61:505-514
  80. Rindt H, Gulick J, Knotts S, Neuman J, Robbins J: In vivo analysis of the murine fP-myosin heavy chain gene promoter. J Biol Chem 1993;268:5332-5338
  81. Eguchi Y, Itoh T, Tomizawa J-I: Antisense RNA. Annu Rev Bio- chem 1991;60:631-652
  82. Pennock G, Raya T, Bahl JJ, Goldman S, Morkin E: Cardiac effects of 3,5-diiodothyropropionic acid, a thyroid hormone analog with inotropic selectivity. J Pharmacol Exp Ther 1992;263:163-169
  83. Stratford-Perricaudet LD, Makeh I, Perricaudet M, Brand P: Widespread long-term gene transfer to mouse skeletal muscles and heart. J Clin Invest 1992;90:626-630 4331-4336 KEYWORDS -Research Advances Series -genes

Authors
Morkin, E.
Affiliations
University of Arizona (US)
Corresponding author
Morkin, E
Venue
Circulation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
1993-05
Volume
87
Issue
5
Pages
1451-1460
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
DOI
10.1161/01.cir.87.5.1451
OpenAlex
W1994325234
Cited by
199
References
72
Citations by year
2025: 1 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 8 · 2020: 7 · 2019: 3 · 2018: 3 · 2017: 1 · 2016: 4 · 2015: 6 · 2014: 9 · 2013: 7 · 2012: 7
FWCI
1.12
Type
journal article
Language
en
Open access
Locations
  • Circulation (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5p01hl020984-21)
  • National Heart, Lung, and Blood Institute (HL-20984)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
Keywords
myosin heavy chain gene, alpha-myosin heavy chain, beta-myosin heavy chain, thyroid hormone regulation, transcriptional regulation, promoter elements, muscle-specific expression, transgenic animals, chimeric plasmids
MeSH terms
Animals, Base Sequence, Gene Expression Regulation, Heart, Humans, Molecular Sequence Data, Myosins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review