Summary
Dystrophin is the product of the Duchenne muscular dystrophy (DMD) gene. Dystrophin-related protein (utrophin), an autosomal homologue of dystrophin, was studied in skeletal muscle from normal fetuses aged 9–26 weeks and one stillbirth of 41 weeks' gestation, and compared with low- and high-risk DMD fetuses aged 9–20 weeks. Utrophin was present at the sarcolemma from before 9 weeks' gestation, although there was variability in intensity both within and between myotubes. Sarcolemmal immunolabelling became more uniform, and levels of utrophin increased to a maximum at approximately 17–18 weeks. Levels then declined, until by 26 weeks sarcolemmal labelling was negligible and levels were similar to adult control muscle. By 41 weeks there was virtually no sarcolemmal labelling, although immunolabelling of capillaries was bright. Similar results were obtained with normal and DMD fetal muscle. Utrophin is therefore expressed in the presence and absence of dystrophin and down-regulated before birth in normal fetal muscle fibres. Samples were not available to determine whether or when, utrophin levels decline in DMD fetal muscle. On Western blots, utrophin was shown to have a smaller relative molecular mass than adult dystrophin, but similar to the fetal isoform. Blood vessels were brightly immunolabelled at all ages, although utrophin immunolabelling of peripheral nerves increased with gestational age.
Similar content being viewed by others
References
Adams,R. D.,Denny-Brown,D. &Pearson,C. M. (1954) Embryology and histology of skeletal muscle. InDiseases of Muscle. Ch. 1, pp. 3–43. New York: Harper and Brothers.
Appleyard,S. T.,Dunn,M. J.,Dubowitz,V.,Scott,M. L.,Pittman,S. J. &Shotton,D. M. (1984) Monoclonal antibodies detect a spectrin-like protein in normal and dystrophic human muscle.Proc. Natl Acad. Sci. USA 81, 776–80.
Arahata,K.,Hoffman,E. P.,Kunkel,L. M.,Ishiura,S.,Tsukahara,T.,Ishihara,T.,Sunohara,N.,Nonaka,I.,Ozawa,E. &Sugita,H. (1988) Immunostaining of skeletal and cardiac muscle surface membrane with antibody against Duchenne muscular dystrophy.Nature 333, 861–3.
Bonilla,E.,Samitt,C. E.,Miranda,A. F.,Hays,A. P.,Salviati,G.,Dimauro,S.,Kunkel,L. M.,Hoffman,E. P. &Rowland,L. P. (1988) Duchenne muscular dystrophy: deficiency of dystrophin at the muscle cell surface.Cell 54, 447–52.
Buckle,V. J.,Guenet,J. L.,Simon-Chazottes,D.,Love,D. R. &Davies,K. E. (1990) Localisation of a dystrophin-related autosomal gene to 6q24 in man, and to mouse chromosome 10 in the region of the dystrophia muscularis (dy) locus.Hum. Genet. 85, 324–6.
Campbell,K. P. &Kahl,S. D. (1989) Association of dystrophin and an integral membrane glycoprotein.Nature 338, 259–62.
Clerk,A.,Rodillo,E.,Heckmatt,J. Z.,Dubowitz,V.,Strong,P. N. &Sewry,C. A. (1991) Characterisation of dystrophin in carriers of Duchenne muscular dystrophy.J. Neurol. Sci. 102, 197–205.
Clerk,A.,Sewry,C. A.,Dubowitz,V. &Strong,P. N. (1992a) Characterisation of dystrophin in foetuses at risk for Duchenne muscular dystrophy.J. Neurol. Sci. 111, 82–91.
Clerk,A.,Strong,P. N. &Sewry,C. A. (1992b). Characterisation of dystrophin during development of human skeletal muscle.Development 114, 395–402.
Ervasti,J. M. &Campbell,K. P. (1991) Membrane organization of the dystrophin-glycoprotein complex.Cell 66, 1121–31.
Helliwell,T. R.,Nguyen,T. M.,Morris,G. E. &Davies,K. E. (1992a) The dystrophin-related protein, utrophin, is expressed on the sarcolemma of regenerating human skeletal muscle fibres in dystrophies and inflammatory myopathies.Neuromusc. Disorders 2, 177–184.
Helliwell,T. R.,Ellis,J. M.,Mountford,R. C.,Appleton,R. E. &Morris,G. E. (1992b) A truncated dystrophin lacking the C-terminal domains is localized at the muscle membrane.Am. J. Hum. Genet. 50, 508–14.
Hoffman,E. P.,Brown,R.H. &Kunkel,L. M. (1987) Dystrophin: the protein product of the Duchenne muscular dystrophy locus.Cell 51, 919–28.
Hoffman,E. P.,Garcia,C. A.,Chamberlain,J. S.,Angelini,C.,Lupski,J. R. &Fenwick,R. (1991) Is the carboxy terminus of dystrophin required for membrane association? A novel case of Duchenne muscular dystrophy.Ann. Neurol. 30, 605–10.
Khurana,T. S.,Hoffman,E. P. &Kunkel,L. M. (1990) Identification of a chromosome 6-encoded dystrophin-related protein.J. Biol. Chem. 265, 16 717–20.
Khurana,T. S.,Watkins,S. C.,Chafey,P.,Chelly,J.,Tome,F. M. S.,Fardeau,M.,Kaplan,J.-C. &Kunkel,L. M. (1991) Immunolocalization and developmental expression of dystrophin related protein in skeletal muscle.Neuromusc. Disorders 1, 185–94.
Koenig,M.,Hoffman,E. P.,Bertelson,C. J.,Monaco,A. P.,Feener,C. &Kunkel,L. M. (1987) Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals.Cell 50, 509–17.
Koenig,M.,Monaco,A. P. &Kunkel,L. M. (1988) The complete sequence of dystrophin predicts a rod-shaped cytoskeletal protein.Cell 53, 219–28.
Love,D. R.,Hill,D. F.,Dickson,G.,Spurr,N. K.,Byth,B. C.,Marsden,R. F.,Walsh,F. S.,Edwards,Y. H. &Davies,K. E. (1989) An autosomal transcript in skeletal muscle with homology to dystrophin.Nature 339, 55–8.
Love,D. R.,Morris,G. E.,Ellis,J. M.,Fairbrother,U.,Marsden,R. F.,Bloomfield,J. F.,Edwards,Y. H.,Slater,C. P.,Parry,D. J. &Davies,K. E. (1991) Tissue distribution of the dystrophin-related gene product and expression in themdx anddy mouse.Proc. Natl Acad. Sci. USA 88, 3243–7.
Mcdouall,R.,Dunn,M. J. &Dubowitz,V. (1989) The expression of class I and class II MHC antigens in neuromuscular diseases.J. Neurol Sci. 89, 213–26.
Matsumura,K.,Ervasti,J. M.,Ohlendieck,K.,Kahl,S. D. &Campbell,K. P. (1992) Association of dystrophin-related protein with dystrophin-associated proteins inmdx mouse muscle.Nature 360, 588–91.
Nguyen,T. M.,Ellis,J. M.,Love,D. R.,Davies,K. E.,Gatter,K. C.,Dickson,G. &Morris,G. E. (1991) Localization of the DMDL gene-encoded dystrophin-related protein using a panel of nineteen monoclonal antibodies: presence at neuromuscular junctions, in the sarcolemma of dystrophic skeletal muscle, in vascular and other smooth muscles, and in proliferating brain cell lines.J. Cell Biol. 115, 1695–700.
Ohlendieck,K.,Ervasti,J. M.,Matsumara,K.,Kahl,S. D.,Leveille,C. J. &Campbell,K. P. (1991a) Dystrophin-related protein is localized to neuromuscular junctions of adult skeletal muscle.Neuron 7, 499–508.
Ohlendieck,K.,Ervasti,J. M.,Snook,J. B. &Campbell,K. P. (1991b) Dystrophin-glycoprotein complex is highly enriched in isolated skeletal muscle sarcolemma.J. Cell Biol. 112, 135–48.
Récan,D.,Chafey,P.,Letureq,F.,Hugnot,J.-P.,Vincent,N.,Tomé,F.,Collin,H.,Simon,D.,Czernichow,P.,Nicholson,L. V. B.,Fardeau,M.,Kaplan,J.-C. &Chelly,J. (1992) Are cysteine-rich and COOH-terminal domains of dystrophin critical for sarcolemmal localization?J. Clin. Invest. 89, 712–6.
Sherratt,T. G.,Vulliamy,T. &Strong,P. N. (1992). Evolutionary conservation of the dystrophin central rod domain.Biochem. J. 287, 755–9.
Takemitsu,M.,Ishiura,S.,Koga,T.,Kamakura,K.,Arahata,K.,Nonaka,I. &Sugita,H. (1991) Dystrophin-related protein in the fetal and denervated skeletal muscles of normal andmdx mice.Biochem. Biophys. Res. Comm. 180, 1179–86.
Tanaka,H.,Ishiguro,T.,Eguchi,C.,Saito,K. &Ozawa,E. (1991) Expression of a dystrophin-related protein associated with the skeletal muscle cell membrane.Histochemistry 96, 1–5.
Tinsley,J. M.,Blake,D. J.,Roche,A.,Fairbrother,U.,Riss,J.,Byth,B. C.,Knight,A. E.,Kendrick-Jones,J.,Suthers,G. K.,Love,D. R.,Edwards,Y.H. &Davies,K. E. (1992) Primary structure of dystrophin-related protein.Nature 360, 591–3.
Voit,T.,Haas,K.,Leger,J. O. C.,Pons,F. &Leger,J. J. (1991) Xp21 dystrophin and 6q dystrophin-related protein. Comparative immunolocalization using multiple antibodies.Am. J. Pathol. 139, 969–76.
Zubrzycka-Gaarn,E. E.,Bulman,D. E.,Karpati,G.,Burghes,A. H. M.,Belfall,B.,Klamut,H. J.,Talbot,J.,Hodges,R. S.,Ray,P. N. &Worton,R. G. (1988) The Duchenne muscular dystrophy gene product is localized in sarcolemma of human skeletal muscle.Nature 333, 466–9.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Clerk, A., Morris, G.E., Dubowitz, V. et al. Dystrophin-related protein, utrophin, in normal and dystrophic human fetal skeletal muscle. Histochem J 25, 554–561 (1993). https://doi.org/10.1007/BF02388063
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF02388063