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Gene Review

Ckm  -  creatine kinase, muscle

Mus musculus

Synonyms: Ckmm, Creatine kinase M chain, Creatine kinase M-type, M-CK, MCK
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Disease relevance of Ckm

  • Both M-CK(-)/(-) and CK(-)/(-) showed increased phosphomonoester levels during ischemia, most likely reflecting adaptation to a more efficient utilization of glycogenolysis [1].
  • In contrast to the cell type- and differentiation-specific expression of the upstream enhancer, the MCK promoter was able to function in myoblasts and myotubes and in nonmyogenic cell lines when combined with the simian virus 40 enhancer [2].
  • Transgenic (MCK-CD36) mice had a slightly lower body weight than control litter mates [3].
  • In vitro, we observed high-level, but unrestricted, gene expression from the cytomegalovirus (CMV) promoter unlike expression from the MCK promoter which was weak but restricted to myofibers [4].
  • Therefore, the MCK/SV40 promoter may provide the basis for development of an effective transgene expression cassette for treatment of congenital protein deficiencies in which therapeutic proteins are recognized as foreign by the host immune system [5].

High impact information on Ckm

  • To understand the physiological role of the creatine kinase-phosphocreatine (CK-PCr) system in muscle bioenergetics, a null mutation of the muscle CK (M-CK) gene was introduced into the germline of mice [6].
  • In vivo protein-DNA interactions at the developmentally regulated enhancer of the mouse muscle creatine kinase (MCK) gene were examined by a newly developed polymerase chain reaction (PCR) footprinting procedure [7].
  • Several footprints were detected in terminally differentiated muscle cells where the MCK gene is actively transcribed [7].
  • Mice homozygous for this M-CK allele (M-CKI/I) have a 3-fold reduction of dimeric muscle CK enzyme activity, whereas compound heterozygotes with the null M-CK allele (M-CKI/-) display a 6-fold reduction [8].
  • In the absence of an authentic target for the MASH proteins, we examined their DNA binding and transcriptional regulatory activity by using a binding site (the E box) from the muscle creatine kinase (MCK) gene, a target of MyoD [9].

Biological context of Ckm

  • Transcriptional regulatory element X (Trex) is a positive control site within the Muscle creatine kinase (MCK) enhancer [10].
  • It has been proposed that the myogenic factors, MyoD1 and myogenin, directly regulate MCK gene expression in the mouse by binding to its enhancer [11].
  • Addition of IGF-I or LiCl stimulated myogenesis, evidenced by increased myotube formation, muscle creatine kinase (MCK) activity, and troponin I (TnI) promoter transactivation during differentiation [12].
  • Using targeting constructs based on strain 129/Sv isogenic DNA we managed to ablate the essential exons of the B-CK and M-CK genes at reasonably high frequencies [13].
  • Hearts from wild-type, MCK-/-, and M/MtCK-/- mice had comparable baseline function and responded to 10 minutes of increased heart rate and perfusate Ca2+ with similar increases in rate-pressure product (48+/-5%, 42+/-6%, and 51+/-6%, respectively) [14].

Anatomical context of Ckm

  • Cell culture and transgenic studies indicate that the Trex site is important for MCK expression in skeletal and cardiac muscle [10].
  • Our purpose was to determine whether hearts from mice bioengineered to lack either the M isoform of creatine kinase (MCK-/- mice) or both the M and mitochondrial isoforms (M/MtCK-/- mice) have deficits in cardiac contractile function and energetics, which have previously been reported in skeletal muscle from these mice [14].
  • We performed transient transfections of CAT reporter constructs, driven by the MCK promoter with variable lengths of 5'-flanking sequence, into primary cultures of embryonic and fetal muscle cells [15].
  • As a test system we compared hindlimb muscle of knockout mice lacking the cytosolic M-type (M-CK(-)/(-)), the mitochondrial ScMit-type (ScCKmit(-)/(-)), or both creatine kinase isoenzymes (CK(-)/(-)), and in vivo 31P-NMR was used to monitor metabolic responses during and after an ischemic period [1].
  • Unexpectedly, however, MASH1 and MASH2 also activate transcription of both exogenous and endogenous MCK in transfected C3H/10T1/2 fibroblasts [9].

Associations of Ckm with chemical compounds

  • Impaired intracellular energetic communication in muscles from creatine kinase and adenylate kinase (M-CK/AK1) double knock-out mice [16].
  • An analysis of actomyosin complexes in vitro demonstrated that one of the consequences of M-CK and AK1 deficiency is hampered phosphoryl delivery to the actomyosin ATPase, resulting in a loss of contractile performance [16].
  • To study the physiological role of the creatine kinase/phosphocreatine (CK/PCr) system in cells and tissues with a high and fluctuating energy demand we have concentrated on the site-directed inactivation of the B- and M-CK genes encoding the cytosolic CK protein subunits [13].
  • Finally, combined loss of M- and Mt-CK (but not loss of only M-CK) prevented the amount of free energy released from ATP hydrolysis from increasing when pyruvate was provided as a substrate for oxidative phosphorylation [17].
  • Finally, overexpression of myogenin rescued the inhibitory effect of rapamycin on MCK gene transcription, whereas it failed to rescue the inhibitory effect of LY294002 and Akt1 [18].

Physical interactions of Ckm

  • Like myogenic bHLH proteins, the MASH proteins form heterooligomers with E12 that bind the MCK E box with high affinity in vitro [9].

Regulatory relationships of Ckm


Other interactions of Ckm

  • The M isoform of creatine kinase (MCK), the striated muscle-specific isoform, is expressed later than BCK [11].
  • Herein, we show that simultaneous disruption of the genes for the cytosolic M-CK- and AK1 isoenzymes compromises intracellular energetic communication and severely reduces the cellular capability to maintain total ATP turnover under muscle functional load [16].
  • METHODS: CK-deficient mice (CK KO) were examined by cardiac magnetic resonance imaging (MRI) to determine left ventricular volumes, ejection fraction, and mass: ten wild-type (WT), 6 mitochondrial CK KO (Mito-CK-/-), 10 cytosolic CK KO (M-CK-/-), and 10 mice with combined KO (M/Mito-CK-/-) [22].
  • The cis-acting elements, MEF-2, E boxes and A/T rich elements present in the enhancer region of the mouse MCK gene are known to regulate the expression of the gene [23].
  • Deletion analysis indicated that the C-terminal 15 amino acids of Id3 are critical for the full inhibitory activity while deleting up to 42 residues from the C-terminus of the related protein, Id2, did not affect its ability to inhibit the MCK reporter gene [24].

Analytical, diagnostic and therapeutic context of Ckm

  • Fifty-two days after chronic denervation, the number of molecules of MCK/ng total RNA in both muscles (determined with competitive PCR) decreased, with the soleus muscle being more affected [25].
  • We have used gel mobility shift assays to characterize the trans-acting factors that interact with a region of the MCK gene containing the 5' enhancer [26].
  • Myostatin mRNA and protein, measured by RT-PCR and Western blot, respectively, were significantly higher in gastrocnemius, quadriceps, and tibialis anterior of MCK/Mst-transgenic mice compared with wild-type mice [27].
  • Male MCK/Mst-transgenic mice had 18-24% lower hind- and forelimb muscle weight and 18% reduction in quadriceps and gastrocnemius fiber cross-sectional area and myonuclear number (immunohistochemistry) than wild-type male mice [27].
  • Proliferating myoblasts and differentiated myofiber cultures were analyzed via SDS-PAGE, immunochemical, and PCR methods for expression of myosin heavy chains (MyHC) and muscle creatine kinase (MCK) as indices of muscle fiber type [28].


  1. Effects of ischemia on skeletal muscle energy metabolism in mice lacking creatine kinase monitored by in vivo 31P nuclear magnetic resonance spectroscopy. in 't Zandt, H.J., Oerlemans, F., Wieringa, B., Heerschap, A. NMR in biomedicine. (1999) [Pubmed]
  2. Identification of upstream and intragenic regulatory elements that confer cell-type-restricted and differentiation-specific expression on the muscle creatine kinase gene. Sternberg, E.A., Spizz, G., Perry, W.M., Vizard, D., Weil, T., Olson, E.N. Mol. Cell. Biol. (1988) [Pubmed]
  3. Muscle-specific overexpression of FAT/CD36 enhances fatty acid oxidation by contracting muscle, reduces plasma triglycerides and fatty acids, and increases plasma glucose and insulin. Ibrahimi, A., Bonen, A., Blinn, W.D., Hajri, T., Li, X., Zhong, K., Cameron, R., Abumrad, N.A. J. Biol. Chem. (1999) [Pubmed]
  4. DNA immunization utilizing a herpes simplex virus type 2 myogenic DNA vaccine protects mice from mortality and prevents genital herpes. Gebhard, J.R., Zhu, J., Cao, X., Minnick, J., Araneo, B.A. Vaccine (2000) [Pubmed]
  5. Muscle creatine kinase/SV40 hybrid promoter for muscle-targeted long-term transgene expression. Takeshita, F., Takase, K., Tozuka, M., Saha, S., Okuda, K., Ishii, N., Sasaki, S. Int. J. Mol. Med. (2007) [Pubmed]
  6. Skeletal muscles of mice deficient in muscle creatine kinase lack burst activity. van Deursen, J., Heerschap, A., Oerlemans, F., Ruitenbeek, W., Jap, P., ter Laak, H., Wieringa, B. Cell (1993) [Pubmed]
  7. In vivo footprinting of a muscle specific enhancer by ligation mediated PCR. Mueller, P.R., Wold, B. Science (1989) [Pubmed]
  8. Creatine kinase (CK) in skeletal muscle energy metabolism: a study of mouse mutants with graded reduction in muscle CK expression. van Deursen, J., Ruitenbeek, W., Heerschap, A., Jap, P., ter Laak, H., Wieringa, B. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  9. DNA binding and transcriptional regulatory activity of mammalian achaete-scute homologous (MASH) proteins revealed by interaction with a muscle-specific enhancer. Johnson, J.E., Birren, S.J., Saito, T., Anderson, D.J. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  10. Quantitative proteomic identification of six4 as the trex-binding factor in the muscle creatine kinase enhancer. Himeda, C.L., Ranish, J.A., Angello, J.C., Maire, P., Aebersold, R., Hauschka, S.D. Mol. Cell. Biol. (2004) [Pubmed]
  11. Developmental regulation of creatine kinase gene expression by myogenic factors in embryonic mouse and chick skeletal muscle. Lyons, G.E., Mühlebach, S., Moser, A., Masood, R., Paterson, B.M., Buckingham, M.E., Perriard, J.C. Development (1991) [Pubmed]
  12. Inhibition of glycogen synthase kinase-3beta activity is sufficient to stimulate myogenic differentiation. van der Velden, J.L., Langen, R.C., Kelders, M.C., Wouters, E.F., Janssen-Heininger, Y.M., Schols, A.M. Am. J. Physiol., Cell Physiol. (2006) [Pubmed]
  13. Approaching the multifaceted nature of energy metabolism: inactivation of the cytosolic creatine kinases via homologous recombination in mouse embryonic stem cells. van Deursen, J., Wieringa, B. Mol. Cell. Biochem. (1994) [Pubmed]
  14. Impaired cardiac energetics in mice lacking muscle-specific isoenzymes of creatine kinase. Saupe, K.W., Spindler, M., Tian, R., Ingwall, J.S. Circ. Res. (1998) [Pubmed]
  15. Absence of MEF2 binding to the A/T-rich element in the muscle creatine kinase (MCK) enhancer correlates with lack of early expression of the MCK gene in embryonic mammalian muscle. Ferrari, S., Molinari, S., Melchionna, R., Cusella-De Angelis, M.G., Battini, R., De Angelis, L., Kelly, R., Cossu, G. Cell Growth Differ. (1997) [Pubmed]
  16. Impaired intracellular energetic communication in muscles from creatine kinase and adenylate kinase (M-CK/AK1) double knock-out mice. Janssen, E., Terzic, A., Wieringa, B., Dzeja, P.P. J. Biol. Chem. (2003) [Pubmed]
  17. Kinetic, thermodynamic, and developmental consequences of deleting creatine kinase isoenzymes from the heart. Reaction kinetics of the creatine kinase isoenzymes in the intact heart. Saupe, K.W., Spindler, M., Hopkins, J.C., Shen, W., Ingwall, J.S. J. Biol. Chem. (2000) [Pubmed]
  18. Akt1 and Akt2 differently regulate muscle creatine kinase and myogenin gene transcription in insulin-induced differentiation of C2C12 myoblasts. Sumitani, S., Goya, K., Testa, J.R., Kouhara, H., Kasayama, S. Endocrinology (2002) [Pubmed]
  19. Lack of requirement for presenilin1 in Notch1 signaling. Berechid, B.E., Thinakaran, G., Wong, P.C., Sisodia, S.S., Nye, J.S. Curr. Biol. (1999) [Pubmed]
  20. p53 protein is activated during muscle differentiation and participates with MyoD in the transcription of muscle creatine kinase gene. Tamir, Y., Bengal, E. Oncogene (1998) [Pubmed]
  21. bFGF induces BCK promoter-driven expression in muscle via increased binding of a nuclear protein. Kim, L., Steves, A., Collins, M., Fu, J., Ritchie, M.E. Am. J. Physiol. (1997) [Pubmed]
  22. Creatine kinase knockout mice show left ventricular hypertrophy and dilatation, but unaltered remodeling post-myocardial infarction. Nahrendorf, M., Spindler, M., Hu, K., Bauer, L., Ritter, O., Nordbeck, P., Quaschning, T., Hiller, K.H., Wallis, J., Ertl, G., Bauer, W.R., Neubauer, S. Cardiovasc. Res. (2005) [Pubmed]
  23. Expression of muscle creatine kinase gene of mice and interaction of nuclear proteins with MEF-2, E boxes and A/T-rich elements during aging. Shanti, K., Kanungo, M.S. Mol. Biol. Rep. (2004) [Pubmed]
  24. Inhibition of muscle-specific gene expression by Id3: requirement of the C-terminal region of the protein for stable expression and function. Chen, B., Han, B.H., Sun, X.H., Lim, R.W. Nucleic Acids Res. (1997) [Pubmed]
  25. Effect of chronic denervation and denervation-reinnervation on cytoplasmic creatine kinase transcript accumulation. Washabaugh, C.H., Ontell, M.P., Kant, J.A., Daood, M.J., Watchko, J.F., Watkins, S.C., Ontell, M. J. Neurobiol. (2001) [Pubmed]
  26. Identification of a myocyte nuclear factor that binds to the muscle-specific enhancer of the mouse muscle creatine kinase gene. Buskin, J.N., Hauschka, S.D. Mol. Cell. Biol. (1989) [Pubmed]
  27. Lower skeletal muscle mass in male transgenic mice with muscle-specific overexpression of myostatin. Reisz-Porszasz, S., Bhasin, S., Artaza, J.N., Shen, R., Sinha-Hikim, I., Hogue, A., Fielder, T.J., Gonzalez-Cadavid, N.F. Am. J. Physiol. Endocrinol. Metab. (2003) [Pubmed]
  28. Effect of muscle origin and phenotype on satellite cell muscle-specific gene expression. LaFramboise, W.A., Guthrie, R.D., Scalise, D., Elborne, V., Bombach, K.L., Armanious, C.S., Magovern, J.A. J. Mol. Cell. Cardiol. (2003) [Pubmed]
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