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Gene Review

MYF6  -  myogenic factor 6 (herculin)

Homo sapiens

Synonyms: BHLHC4, CNM3, Class C basic helix-loop-helix protein 4, MRF4, Muscle-specific regulatory factor 4, ...
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Disease relevance of MYF6

  • In a boy with myopathy and an increase of muscle fibres with central nuclei we detected a heterozygous 387G-->T nucleotide transversion in the MYF6 gene (MIM*159991) [1].
  • This mutation is normally associated with a mild to moderate course of Becker muscular dystrophy but the father suffered from a severe course of Becker muscular dystrophy suggesting MYF6 as a modifier [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].

High impact information on MYF6

  • Skeletal myogenesis is regulated by a group of transcription factors (MyoD, myogenin, myf5, and myf6) that are "basic helix-loop-helix" proteins that bind to the promoters of muscle-specific genes and promote their expression [3].
  • Skeletal myogenesis is associated with the activation of four muscle regulatory factors (MRFs): Myf5, MyoD, Myogenin and MRF4 [4].
  • MRF4 is phosphorylated in vitro and in vivo by p38 on two serines (Ser31 and Ser42) located in the N-terminal transactivation domain, resulting in reduced MRF4-mediated transcriptional activity [4].
  • In contrast, nonphosphorylatable MRF4 mutants display increased transcriptional activity and are able to advance both myoblast fusion and differentiation [4].
  • We propose that repression of MRF4 activity by p38 phosphorylation may represent a new mechanism for the silencing of specific muscle genes at the terminal stages of muscle differentiation [4].

Biological context of MYF6

  • Comparative sequence analysis of putative regulatory sequences in swine revealed a total of 21 single nucleotide polymorphisms (SNP) including 1 and 6 SNPs new for the promoters of MYF5 and MYF6, respectively [5].
  • Protein-protein interaction of mutant MYF6 was reduced, and DNA-binding potential and transactivation capacity were abolished, thus demonstrating MYF6 haploinsufficiency [1].
  • Assignment of the human myogenic factors 5 and 6 (MYF5, MYF6) gene cluster to 12q21 by in situ hybridization and physical mapping of the locus between D12S350 and D12S106 [6].
  • Moreover, muscle-specific CAT reporter constructs containing either the human myosin light chain (MLC) enhancer or the promoter of the embryonic myosin light chain gene are activated in NIH 3T3 fibroblasts or in CV1 kidney cells by cotransfection of Myf-6 expression vehicles [7].
  • Constitutive expression of Myf-6 cDNA in C3H 10T1/2 fibroblasts establishes the muscle phenotype at a similar frequency to the previously characterized myogenic factors [7].

Anatomical context of MYF6

  • Myf-6 cDNAs were isolated from human and mouse skeletal muscle, the only tissue in which expression of the corresponding mRNA was observed [7].
  • In contrast to human primary muscle cell cultures which express moderate levels of Myf-6 mRNA, most established rodent muscle cell lines completely lack this mRNA [7].
  • 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].
  • On this basis, MyoD and Myf-5 are classified as primary MRFs, as they are required for the determination of myoblasts, and myogenin and MRF4 are classified as secondary MRFs, as they likely function during terminal differentiation [8].
  • Myf 5 and MRF 4 transcripts are detected in stage 15 forelimbs, which is the earliest stage limb in which myogenic precursors have been detected following their migration from the somite [9].

Associations of MYF6 with chemical compounds

  • 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 [10].

Regulatory relationships of MYF6

  • Myogenic 10T1/2 cells, however, induced by the expression of either pEMSV-Myf-4 or pEMSV-Myf-5 activate their endogenous mouse Myf-6 gene [7].
  • Moreover, transient expression of Myf6 induced significant activation on the ACCbeta promoter or an artificial promoter harboring this novel cis-element [11].

Other interactions of MYF6

  • The four human muscle regulatory helix-loop-helix proteins Myf3-Myf6 exhibit similar hetero-dimerization and DNA binding properties [12].
  • MyoD and MRF4 expression was not altered under either condition and no myf5 expression was detected [13].
  • In response to RE, there was a main time effect (P < 0.05) for the YW and OW combined in the upregulation of MyoD (2.0-fold) and MRF4 (1.4-fold) and in the downregulation of myostatin (2.2-fold) [14].
  • Myogenin, MyoD, and MRF4 mRNA levels were elevated (P < 0.005) by 100-400% 0-24 h postexercise [2].
  • Therefore, increases in myogenin and MRF-4 mRNA and protein may play a role in increasing myosin heavy chain expression, already shown to occur with Cr supplementation [15].

Analytical, diagnostic and therapeutic context of MYF6


  1. Heterozygous myogenic factor 6 mutation associated with myopathy and severe course of Becker muscular dystrophy. Kerst, B., Mennerich, D., Schuelke, M., Stoltenburg-Didinger, G., von Moers, A., Gossrau, R., van Landeghem, F.K., Speer, A., Braun, T., Hübner, C. Neuromuscul. Disord. (2000) [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. Rhabdomyosarcomas do not contain mutations in the DNA binding domains of myogenic transcription factors. Anand, G., Shapiro, D.N., Dickman, P.S., Prochownik, E.V. J. Clin. Invest. (1994) [Pubmed]
  4. Phosphorylation of MRF4 transactivation domain by p38 mediates repression of specific myogenic genes. Suelves, M., Lluís, F., Ruiz, V., Nebreda, A.R., Muñoz-Cánoves, P. EMBO J. (2004) [Pubmed]
  5. Identification and analysis of putative regulatory sequences for the MYF5/MYF6 locus in different vertebrate species. Maak, S., Neumann, K., Swalve, H.H. Gene (2006) [Pubmed]
  6. Assignment of the human myogenic factors 5 and 6 (MYF5, MYF6) gene cluster to 12q21 by in situ hybridization and physical mapping of the locus between D12S350 and D12S106. Cupelli, L., Renault, B., Leblanc-Straceski, J., Banks, A., Ward, D., Kucherlapati, R.S., Krauter, K. Cytogenet. Cell Genet. (1996) [Pubmed]
  7. Myf-6, a new member of the human gene family of myogenic determination factors: evidence for a gene cluster on chromosome 12. Braun, T., Bober, E., Winter, B., Rosenthal, N., Arnold, H.H. EMBO J. (1990) [Pubmed]
  8. Determination versus differentiation and the MyoD family of transcription factors. Megeney, L.A., Rudnicki, M.A. Biochem. Cell Biol. (1995) [Pubmed]
  9. Myogenic determination factor expression in the developing avian limb bud: an RT-PCR analysis. Lin-Jones, J., Hauschka, S.D. Dev. Biol. (1996) [Pubmed]
  10. 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]
  11. Cloning of human acetyl-CoA carboxylase beta promoter and its regulation by muscle regulatory factors. Lee, J.J., Moon, Y.A., Ha, J.H., Yoon, D.J., Ahn, Y.H., Kim, K.S. J. Biol. Chem. (2001) [Pubmed]
  12. The four human muscle regulatory helix-loop-helix proteins Myf3-Myf6 exhibit similar hetero-dimerization and DNA binding properties. Braun, T., Arnold, H.H. Nucleic Acids Res. (1991) [Pubmed]
  13. cAMP effects on myogenic gene expression in rhabdomyosarcoma cells. Wasserman, L.M., Newsham, I., Huang, H.J., Cavenee, W.K. Exp. Cell Res. (1996) [Pubmed]
  14. Myogenic gene expression at rest and after a bout of resistance exercise in young (18-30 yr) and old (80-89 yr) women. Raue, U., Slivka, D., Jemiolo, B., Hollon, C., Trappe, S. J. Appl. Physiol. (2006) [Pubmed]
  15. 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]
  16. 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]
  17. Molecular mechanisms regulating myogenic determination and differentiation. Perry, R.L., Rudnick, M.A. Front. Biosci. (2000) [Pubmed]
  18. Identification of MRF4, myogenin, and E12 oligomer complexes by chemical cross-linking and two-dimensional gel electrophoresis. Lin, H., Konieczny, S.F. J. Biol. Chem. (1992) [Pubmed]
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