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Gene Review

MYOG  -  myogenin (myogenic factor 4)

Homo sapiens

Synonyms: BHLHC3, Class C basic helix-loop-helix protein 3, MYF4, Myf-4, Myogenic factor 4, ...
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Disease relevance of MYOG

  • Human bHLH transcription factor gene myogenin (MYOG): genomic sequence and negative mutation analysis in patients with severe congenital myopathies [1].
  • The present study shows that myogenin, MyoD, and MRF4 mRNA levels are transiently elevated in human skeletal muscle after a single bout of heavy-resistance training, supporting the idea that the MRFs may be involved in regulating hypertrophy and/or fiber-type transitions [2].
  • The myogenin gene encodes an evolutionarily conserved basic helix-loop-helix transcription (bHLH) factor that is required for differentiation of skeletal muscle, and its homozygous deletion in mice results in perinatal death from respiratory failure due to the lack of muscle fibers [1].
  • Rhabdomyosarcoma (RMS) has deregulated proliferation and is blocked in the differentiation program despite Myf-5, MyoD and myogenin expression [3].
  • Mild hypoxia increased myogenin transcript level [4].

Psychiatry related information on MYOG

  • The Id proteins are negative regulators of several basic-helix-loop-helix (HLH) transcription factors, including the ubiquitous E factors and the tissue-specific myogenin-regulating factors [5].

High impact information on MYOG

  • A myogenin mutant lacking the PKC phosphorylation site is not repressed by FGF, confirming this site as a molecular target for FGF-dependent repression of muscle transcription [6].
  • Myogenin belongs to a family of myogenic helix-loop-helix (HLH) proteins that activate muscle transcription through binding to a conserved DNA sequence associated with numerous muscle-specific genes [6].
  • In this report we provide four lines of evidence indicating that E12/E47-like proteins interact in vivo with the myogenic HLH proteins MyoD and myogenin [7].
  • We have now investigated whether MyoD or myogenin, regulators of muscle-specific gene expression that have a helix-loop-helix motif, can induce the phenotypic conversion observed in heterokaryons [8].
  • As levels of myogenin mRNA rise, those of myf-5 mRNA (the only other member of the MyoD family expressed significantly in L6 myoblasts) fall dramatically, although myf-5 expression is required for the initial elevation of myogenin [9].

Chemical compound and disease context of MYOG


Biological context of MYOG

  • The blocking of the upregulation of myogenin, a transcriptional regulator responsible for the execution of the entire myogenic differentiation program, indicates that CEA expression intercepts the process at a very early stage [14].
  • We have used this assay to investiagate whether myogenin forms homomeric or heteromeric complexes in vivo and to determine whether growth factors and oncogenes that inhibit myogenesis influence myogenin's ability to dimerize [15].
  • Membrane hyperpolarization triggers myogenin and myocyte enhancer factor-2 expression during human myoblast differentiation [16].
  • Immunohistochemical analysis of normal and patient-derived skeletal musculature revealed that Myf4, which is downregulated during normal fetal development, was still present in patient-derived skeletal head muscle, which was also positive for Desmin and sarcomeric actin [17].
  • In vitro and in vivo assays revealed a direct association of Sp1 and myogenin-MyoD mediated by the DNA-binding domain of Sp1 and the HLH motif of myogenin [18].

Anatomical context of MYOG

  • In mouse C2 and P2 muscle cell lines MyoD1 is abundantly synthesized together with myogenin [19].
  • The myogenic conversion of 10T1/2 fibroblasts results in the activation of the endogenous MyoD1 and Myf-4 (myogenin) genes [19].
  • We conclude that the Kir2.1-induced hyperpolarization triggers human myoblast differentiation via the activation of the calcineurin pathway, which, in turn, induces expression/activity of myogenin and MEF2 [20].
  • It is widely thought that myogenin is one of the earliest detectable markers of skeletal muscle differentiation [16].
  • Myogenin, MRF4, MyoD, IGF-IEabc (isoforms a, b, and c) and IGF-IEbc (isoform b and c) mRNA levels were determined in the vastus lateralis muscle by RT-PCR before exercise, immediately after, and 1, 2, 6, 24, and 48 h postexercise [2].

Associations of MYOG with chemical compounds

  • BMP-2 did not efficiently suppress the mRNA expression of muscle-specific genes such as muscle creatine kinase, MyoD, and myogenin, nor did it induce the expression of ALP mRNA in the DeltaBMPR-IA-transfected C2C12 cells [21].
  • In contrast, LY294002, an inhibitor of phosphatidylinositol 3-kinase (a pathway controlling initiation of the myogenic program) that inhibited both myogenin/MEF2 expression and fusion, did not affect Kir2.1 current [16].
  • Following a single bout of exercise at 40% and 75% of VO(2) max, an accumulation of myogenin in myonuclei and not in satellite cells was observed in biopsies from the exercised leg but not in biopsies before exercise and from the resting leg [22].
  • Prmt5 and dimethylated H3R8 (histone 3 arginine 8) are localized at the myogenin promoter in differentiating cells [23].
  • The expression of myogenin (baseline, 6.2 vs. 20.7% after treatment, P < 0.005), examined only in the 300-mg group, increased significantly in muscle fiber nuclei after testosterone treatment, but Numb expression did not change [24].

Physical interactions of MYOG

  • Indeed, nucleosomal histones surrounding a MEF2-binding site in the myogenin gene promoter are highly methylated in undifferentiated myoblasts, when the gene is silent, and become acetylated during muscle differentiation, when the myogenin gene is expressed at high levels [25].
  • Moreover, RD-p16 cells cultured under permissive condition demonstrated differentiated morphology coupled with expressions of myogenin and myosin light chain [26].

Regulatory relationships of MYOG

  • Drugs or antisense reducing Kir2.1 current diminished or suppressed fusion as well as expression/activity of myogenin and MEF2 [16].
  • Unlike mouse myoblasts, forced expression of MEF2A did not synergistically enhance transcription from the myogenin promoter in chick myoblasts, indicating that additional molecular determinants of the block to myogenesis exist [27].
  • In cells which stably express E1a, myogenin expression is completely suppressed while Myf-5 continues to be synthesized normally [10].
  • Here we demonstrate that the expression of the small heat shock protein alphaB-crystallin as well as MyoD and myogenin is induced during myogenic differentiation in C2C12 cells, and these inductions occur at an early stage in the differentiation in vitro [28].
  • Similarly, myogenin and MyoD expression is induced both by U0126 and TPA and is prevented by p38 inhibition [29].

Other interactions of MYOG

  • Mutation of these lysines affects MEF2 DNA binding and transcriptional activity, as well as its synergistic effect with myogenin in myogenic conversion assays [30].
  • Myogenin, MyoD, and MRF4 mRNA levels were elevated (P < 0.005) by 100-400% 0-24 h postexercise [2].
  • Analysis of the oligomerization of myogenin and E2A products in vivo using a two-hybrid assay system [15].
  • M-CK mRNA was correlated with myogenin (r = 0.916) and MRF-4 (r = 0.883) protein (P < 0.05) [31].
  • Interestingly, the patient's fibroblasts also showed some fusion events during trans-differentiation with a comparable expression profile for the MRFs, particularly, with increased expression of Myf4 and p21 [17].
  • We have found that the p38 mitogen-activated protein kinase is required for BRG1 recruitment in TPA-mediated myogenin induction [32].

Analytical, diagnostic and therapeutic context of MYOG

  • The myf3 and the myf4 gene products are correctly translated and accumulated in the nuclei as shown by immunofluorescence analysis [33].
  • Immunohistochemistry was supportive of skeletal muscle differentiation with at least one positive skeletal muscle-specific marker (myoglobin, MyoD1, fast skeletal muscle myosin, or myf4) [34].
  • We have investigated the expression of various genes, which are preferentially expressed in normal muscle tissue or cell culture (actins, myosins, and creatine kinases, and myogenic regulatory genes MyoD, myogenin, MRF4, and Myf5), in embryonal and alveolar subtypes and compared the results to the stages of developing human fetal limb muscle [35].
  • However, after rehabilitation myogenin protein expression was increased in P but not in CR (P < 0.05), whilst MRF4 protein expression was increased in CR but not in P (P < 0.05) [36].
  • In addition, an isokinetic dynamometer was used to measure maximal knee-extension power (Wmax), and needle biopsy samples taken from the vastus lateralis muscle were examined to asses expression of the myogenic transcription factors MyoD, myogenin, Myf5, and MRF4, and muscle fibre diameters [36].


  1. Human bHLH transcription factor gene myogenin (MYOG): genomic sequence and negative mutation analysis in patients with severe congenital myopathies. Tseng, B.S., Cavin, S.T., Hoffman, E.P., Iannaccone, S.T., Mancias, P., Booth, F.W., Butler, I.J. Genomics (1999) [Pubmed]
  2. Resistance exercise alters MRF and IGF-I mRNA content in human skeletal muscle. Psilander, N., Damsgaard, R., Pilegaard, H. J. Appl. Physiol. (2003) [Pubmed]
  3. Muscle regulatory factor MRF4 activates differentiation in rhabdomyosarcoma RD cells through a positive-acting C-terminal protein domain. Sirri, V., Leibovitch, M.P., Leibovitch, S.A. Oncogene (2003) [Pubmed]
  4. Physiological oxygenation status is required for fully differentiated phenotype in kidney cortex proximal tubules. de Laplanche, E., Gouget, K., Cléris, G., Dragounoff, F., Demont, J., Morales, A., Bezin, L., Godinot, C., Perrière, G., Mouchiroud, D., Simonnet, H. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
  5. Synthesis and conformational analysis of Id2 protein fragments: impact of chain length and point mutations on the structural HLH motif. Colombo, N., Cabrele, C. J. Pept. Sci. (2006) [Pubmed]
  6. FGF inactivates myogenic helix-loop-helix proteins through phosphorylation of a conserved protein kinase C site in their DNA-binding domains. Li, L., Zhou, J., James, G., Heller-Harrison, R., Czech, M.P., Olson, E.N. Cell (1992) [Pubmed]
  7. Functional activity of myogenic HLH proteins requires hetero-oligomerization with E12/E47-like proteins in vivo. Lassar, A.B., Davis, R.L., Wright, W.E., Kadesch, T., Murre, C., Voronova, A., Baltimore, D., Weintraub, H. Cell (1991) [Pubmed]
  8. Effect of cell history on response to helix-loop-helix family of myogenic regulators. Schäfer, B.W., Blakely, B.T., Darlington, G.J., Blau, H.M. Nature (1990) [Pubmed]
  9. Growth hormone and the insulin-like growth factor system in myogenesis. Florini, J.R., Ewton, D.Z., Coolican, S.A. Endocr. Rev. (1996) [Pubmed]
  10. Regulation of myogenin expression in normal and transformed myogenic cell lines. Arnold, H.H., Braun, T., Bober, E., Buchberger, A., Winter, B., Salminen, A. Symp. Soc. Exp. Biol. (1992) [Pubmed]
  11. Overexpression of myotonic dystrophy kinase in BC3H1 cells induces the skeletal muscle phenotype. Bush, E.W., Taft, C.S., Meixell, G.E., Perryman, M.B. J. Biol. Chem. (1996) [Pubmed]
  12. Acetylcholine receptor alpha-subunit and myogenin mRNAs in thymus and thymomas. Kornstein, M.J., Asher, O., Fuchs, S. Am. J. Pathol. (1995) [Pubmed]
  13. Immunohistochemical profile of myogenin and MyoD1 does not support skeletal muscle lineage in alveolar soft part sarcoma. Gómez, J.A., Amin, M.B., Ro, J.Y., Linden, M.D., Lee, M.W., Zarbo, R.J. Arch. Pathol. Lab. Med. (1999) [Pubmed]
  14. Human carcinoembryonic antigen, an intercellular adhesion molecule, blocks fusion and differentiation of rat myoblasts. Eidelman, F.J., Fuks, A., DeMarte, L., Taheri, M., Stanners, C.P. J. Cell Biol. (1993) [Pubmed]
  15. Analysis of the oligomerization of myogenin and E2A products in vivo using a two-hybrid assay system. Chakraborty, T., Martin, J.F., Olson, E.N. J. Biol. Chem. (1992) [Pubmed]
  16. Membrane hyperpolarization triggers myogenin and myocyte enhancer factor-2 expression during human myoblast differentiation. Konig, S., Hinard, V., Arnaudeau, S., Holzer, N., Potter, G., Bader, C.R., Bernheim, L. J. Biol. Chem. (2004) [Pubmed]
  17. Myogenin (Myf4) upregulation in trans-differentiating fibroblasts from a congenital myopathy with arrest of myogenesis and defects of myotube formation. Weise, C., Dai, F., Pr??ls, F., Ketelsen, U.P., Dohrmann, U., Kirsch, M., Brand-Saberi, B. Anat. Embryol. (2006) [Pubmed]
  18. Myogenic basic helix-loop-helix proteins and Sp1 interact as components of a multiprotein transcriptional complex required for activity of the human cardiac alpha-actin promoter. Biesiada, E., Hamamori, Y., Kedes, L., Sartorelli, V. Mol. Cell. Biol. (1999) [Pubmed]
  19. Differential expression of myogenic determination genes in muscle cells: possible autoactivation by the Myf gene products. Braun, T., Bober, E., Buschhausen-Denker, G., Kohtz, S., Grzeschik, K.H., Arnold, H.H., Kotz, S. EMBO J. (1989) [Pubmed]
  20. The calcineurin pathway links hyperpolarization (Kir2.1)-induced Ca2+ signals to human myoblast differentiation and fusion. Konig, S., Béguet, A., Bader, C.R., Bernheim, L. Development (2006) [Pubmed]
  21. A kinase domain-truncated type I receptor blocks bone morphogenetic protein-2-induced signal transduction in C2C12 myoblasts. Namiki, M., Akiyama, S., Katagiri, T., Suzuki, A., Ueno, N., Yamaji, N., Rosen, V., Wozney, J.M., Suda, T. J. Biol. Chem. (1997) [Pubmed]
  22. Effects of one bout of endurance exercise on the expression of myogenin in human quadriceps muscle. Kadi, F., Johansson, F., Johansson, R., Sjöström, M., Henriksson, J. Histochem. Cell Biol. (2004) [Pubmed]
  23. The protein arginine methyltransferase Prmt5 is required for myogenesis because it facilitates ATP-dependent chromatin remodeling. Dacwag, C.S., Ohkawa, Y., Pal, S., Sif, S., Imbalzano, A.N. Mol. Cell. Biol. (2007) [Pubmed]
  24. Effects of testosterone supplementation on skeletal muscle fiber hypertrophy and satellite cells in community-dwelling older men. Sinha-Hikim, I., Cornford, M., Gaytan, H., Lee, M.L., Bhasin, S. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  25. Association of class II histone deacetylases with heterochromatin protein 1: potential role for histone methylation in control of muscle differentiation. Zhang, C.L., McKinsey, T.A., Olson, E.N. Mol. Cell. Biol. (2002) [Pubmed]
  26. Restoration of p16INK4A protein induces myogenic differentiation in RD rhabdomyosarcoma cells. Urashima, M., Teoh, G., Akiyama, M., Yuza, Y., Anderson, K.C., Maekawa, K. Br. J. Cancer (1999) [Pubmed]
  27. Inhibition of myogenin expression by activated Raf is not responsible for the block to avian myogenesis. Johnson, S.E., Dorman, C.M., Bolanowski, S.A. J. Biol. Chem. (2002) [Pubmed]
  28. The small heat shock protein alphaB-crystallin inhibits differentiation-induced caspase 3 activation and myogenic differentiation. Ikeda, R., Yoshida, K., Ushiyama, M., Yamaguchi, T., Iwashita, K., Futagawa, T., Shibayama, Y., Oiso, S., Takeda, Y., Kariyazono, H., Furukawa, T., Nakamura, K., Akiyama, S., Inoue, I., Yamada, K. Biol. Pharm. Bull. (2006) [Pubmed]
  29. p21WAF1 expression induced by MEK/ERK pathway activation or inhibition correlates with growth arrest, myogenic differentiation and onco-phenotype reversal in rhabdomyosarcoma cells. Ciccarelli, C., Marampon, F., Scoglio, A., Mauro, A., Giacinti, C., De Cesaris, P., Zani, B.M. Mol. Cancer (2005) [Pubmed]
  30. Myocyte enhancer factor 2 acetylation by p300 enhances its DNA binding activity, transcriptional activity, and myogenic differentiation. Ma, K., Chan, J.K., Zhu, G., Wu, Z. Mol. Cell. Biol. (2005) [Pubmed]
  31. Effects of oral creatine and resistance training on myogenic regulatory factor expression. Willoughby, D.S., Rosene, J.M. Medicine and science in sports and exercise. (2003) [Pubmed]
  32. Sequential recruitment of PCAF and BRG1 contributes to myogenin activation in 12-O-tetradecanoylphorbol-13-acetate-induced early differentiation of rhabdomyosarcoma-derived cells. Li, Z.Y., Yang, J., Gao, X., Lu, J.Y., Zhang, Y., Wang, K., Cheng, M.B., Wu, N.H., Zhang, Y., Wu, Z., Shen, Y.F. J. Biol. Chem. (2007) [Pubmed]
  33. TPA-induced differentiation of human rhabdomyosarcoma cells: expression of the myogenic regulatory factors. Bouché, M., Senni, M.I., Grossi, A.M., Zappelli, F., Polimeni, M., Arnold, H.H., Cossu, G., Molinaro, M. Exp. Cell Res. (1993) [Pubmed]
  34. Pleomorphic rhabdomyosarcoma in adults: a clinicopathologic study of 38 cases with emphasis on morphologic variants and recent skeletal muscle-specific markers. Furlong, M.A., Mentzel, T., Fanburg-Smith, J.C. Mod. Pathol. (2001) [Pubmed]
  35. Muscle-specific gene expression in rhabdomyosarcomas and stages of human fetal skeletal muscle development. Tonin, P.N., Scrable, H., Shimada, H., Cavenee, W.K. Cancer Res. (1991) [Pubmed]
  36. Oral creatine supplementation facilitates the rehabilitation of disuse atrophy and alters the expression of muscle myogenic factors in humans. Hespel, P., Op't Eijnde, B., Van Leemputte, M., Ursø, B., Greenhaff, P.L., Labarque, V., Dymarkowski, S., Van Hecke, P., Richter, E.A. J. Physiol. (Lond.) (2001) [Pubmed]
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