Mammalian Genome

, Volume 16, Issue 10, pp 739–748 | Cite as

The influence of muscle type and dystrophin deficiency on murine expression profiles

  • Judith N. Haslett
  • Peter B. Kang
  • Mei Han
  • Alvin T. Kho
  • Despina Sanoudou
  • Jay M. Volinski
  • Alan H. Beggs
  • Isaac S. Kohane
  • Louis M. KunkelEmail author
Original Contributions


The phenotypic differences among Duchenne muscular dystrophy patients, mdx mice, and mdx5cv mice suggest that despite the common etiology of dystrophin deficiency, secondary mechanisms have a substantial influence on phenotypic severity. The differential response of various skeletal muscles to dystrophin deficiency supports this hypothesis. To explore these differences, gene expression profiles were generated from duplicate RNA targets extracted from six different skeletal muscles (diaphragm, soleus, gastrocnemius, quadriceps, tibialis anterior, and extensor digitorum longus) from wild-type, mdx, and mdx 5cv mice, resulting in 36 data sets for 18 muscle samples. The data sets were compared in three different ways: (1) among wild-type samples only, (2) among all 36 data sets, and (3) between strains for each muscle type. The molecular profiles of soleus and diaphragm separate significantly from the other four muscle types and from each other. Fiber-type proportions can explain some of these differences. These variations in wild-type gene expression profiles may also reflect biomechanical differences known to exist among skeletal muscles. Further exploration of the genes that most distinguish these muscles may help explain the origins of the biomechanical differences and the reasons why some muscles are more resistant than others to dystrophin deficiency.


Duchenne Muscular Dystrophy Tibialis Anterior Extensor Digitorum Longus Duchenne Muscular Dystrophy Muscle Type 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors thank Marielle Thorne for her assistance. This work was supported by NIH grants P01 NS40828-01A1 (ISK, AHB, LMK), R01 AR44349 (AHB), U01 HL066582-01 (ISK), and K08 NS048180 (PBK), the Muscular Dystrophy Association (PBK, AHB, LMK), the Bernard F. and Alva B. Gimbel Foundation (LMK), the Joshua Frase Foundation (AHB, LMK), and the William Randolph Hearst Foundation (PBK).

Supplementary material

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Supplementary material


  1. Brazma A, Hingamp P, Quackenbush J, et al. (2001) Minimum information about a microarray experiment (MIAME)-toward standards for microarray data. Nat Genet 29: 365-371CrossRefPubMedGoogle Scholar
  2. Bulfield G, Siller WG, Wight PA, Moore KJ (1984) X chromosome-linked muscular dystrophy (mdx) in the mouse. Proc Natl Acad Sci U S A 81: 1189-1192PubMedGoogle Scholar
  3. Burkholder TJ, Fingado B, Baron S, Lieber RL (1994) Relationship between muscle fiber types and sizes and muscle architectural properties in the mouse hindlimb. J Morphol 221: 177-190CrossRefPubMedGoogle Scholar
  4. Butte AJ, Ye J, Haring HU, Stumvoll M, White MF, et al. (2001) Determining significant fold differences in gene expression analysis. Pac Symp Biocomput 6– 17Google Scholar
  5. Campbell WG, Gordon SE, Carlson CJ, et al. (2001) Differential global gene expression in red and white skeletal muscle. Am J Physiol Cell Physiol 280: C763-C768PubMedGoogle Scholar
  6. Chapman VM, Miller DR, Armstrong D, Caskey CT (1989) Recovery of induced mutations for X chromosome-linked muscular dystrophy in mice. Proc Natl Acad Sci U S A 86: 1292-1296PubMedGoogle Scholar
  7. Chen YW, Zhao P, Borup R, Hoffman EP (2000) Expression profiling in the muscular dystrophies: identification of novel aspects of molecular pathophysiology. J Cell Biol 151: 1321-1336CrossRefPubMedGoogle Scholar
  8. Danko I, Chapman V, Wolff JA (1992) The frequency of revertants in mdx mouse genetic models for Duchenne muscular dystrophy. Pediatr Res 32: 128-131PubMedGoogle Scholar
  9. Deconinck N, Rafael JA, Beckers-Bleukx G, Kahn D, Deconinck AE, et al. (1998) Consequences of the combined deficiency in dystrophin and utrophin on the mechanical properties and myosin composition of some limb and respiratory muscles of the mouse. Neuromuscul Disord 8: 362-370CrossRefPubMedGoogle Scholar
  10. Durbeej M, Campbell KP (2002) Muscular dystrophies involving the dystrophin-glycoprotein complex: an overview of current mouse models. Curr Opin Genet Dev 12: 349-361CrossRefPubMedGoogle Scholar
  11. Eisen MB, Spellman PT, Brown PO, Botstein D (1998) Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci U S A 95: 14863-14868CrossRefPubMedGoogle Scholar
  12. Ervasti JM, Campbell KP (1991) Membrane organization of the dystrophin-glycoprotein complex. Cell 66: 1121-1131CrossRefPubMedGoogle Scholar
  13. Ervasti JM, Ohlendieck K, Kahl SD, et al. (1990) Deficiency of a glycoprotein component of the dystrophin complex in dystrophic muscle. Nature 345: 315-319CrossRefPubMedGoogle Scholar
  14. Greenberg SA, Sanoudou D, Haslett JN, et al. (2002) Molecular profiles of inflammatory myopathies. Neurology 59: 1170-1182PubMedGoogle Scholar
  15. Haslett JN, Kunkel LM (2002) Microarray analysis of normal and dystrophic skeletal muscle. Int J Dev Neurosci 20: 359-365CrossRefPubMedGoogle Scholar
  16. Haslett JN, Sanoudou D, Kho AT, et al. (2002) Gene expression comparison of biopsies from Duchenne muscular dystrophy (DMD) and normal skeletal muscle. Proc Natl Acad Sci U S A 99: 15000-15005CrossRefPubMedGoogle Scholar
  17. Haslett JN, Sanoudou D, Kho AT, et al. (2003) Gene expression profiling of Duchenne muscular dystrophy skeletal muscle. Neurogenetics 4: 163-171CrossRefPubMedGoogle Scholar
  18. Hoffman EP, Gorospe JR (1991) The animal models of Duchenne muscular dystrophy: windows on the pathophysiological consequences of dystrophin deficiency. In Ordering the membrane cytoskeleton trilayer, Mooseker MT, Morrow J, eds. (New York: Academic), pp 113-154Google Scholar
  19. Hoffman EP, Brown RH Jr, Kunkel LM (1987) Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 51: 919-928CrossRefPubMedGoogle Scholar
  20. Kaminski HJ, al-Hakim M, Leigh RJ, et al. (1992) Extraocular muscles are spared in advanced Duchenne dystrophy. Ann Neurol 32: 586-588CrossRefPubMedGoogle Scholar
  21. Karpati G, Carpenter S (1986) Small-caliber skeletal muscle fibers do not suffer deleterious consequences of dystrophic gene expression. Am J Med Genet 25: 653-658CrossRefPubMedGoogle Scholar
  22. Khurana TS, Prendergast RA, Alameddine HS, et al. (1995) Absence of extraocular muscle pathology in Duchenne’s muscular dystrophy: role for calcium homeostasis in extraocular muscle sparing. J Exp Med 182: 467-475CrossRefPubMedGoogle Scholar
  23. Koenig M, Monaco AP, Kunkel LM (1988) The complete sequence of dystrophin predicts a rod-shaped cytoskeletal protein. Cell 53: 219-226CrossRefPubMedGoogle Scholar
  24. Matsumura K, Ervasti JM, Ohlendieck K, et al. (1992) Association of dystrophin-related protein with dystrophin-associated proteins in mdx mouse muscle. Nature 360: 588-591CrossRefPubMedGoogle Scholar
  25. McArdle A, Edwards RH, Jackson MJ (1994) Time course of changes in plasma membrane permeability in the dystrophin-deficient mdx mouse. Muscle Nerve 17: 1378-1384CrossRefPubMedGoogle Scholar
  26. Moens P, Baatsen PH, Marechal G (1993) Increased susceptibility of EDL muscles from mdx mice to damage induced by contractions with stretch. J Muscle Res Cell Motil 14: 446-451CrossRefPubMedGoogle Scholar
  27. Noguchi S, Tsukahara T, Fujita M, et al. (2003) cDNA microarray analysis of individual Duchenne muscular dystrophy patients. Hum Mol Genet 12: 595-600CrossRefPubMedGoogle Scholar
  28. Petrof BJ, Stedman HH, Shrager JB, et al. (1993) Adaptations in myosin heavy chain expression and contractile function in dystrophic mouse diaphragm. Am J Physiol 265: C834-C841PubMedGoogle Scholar
  29. Porter JD, Khanna S, Kaminski HJ, et al. (2002) A chronic inflammatory response dominates the skeletal muscle molecular signature in dystrophin-deficient mdx mice. Hum Mol Genet 11: 263-272CrossRefPubMedGoogle Scholar
  30. Porter JD, Baker RS (1996) Muscles of a different “color”: the unusual properties of the extraocular muscles may predispose or protect them in neurogenic and myogenic disease. Neurology 46: 30-37PubMedGoogle Scholar
  31. Porter JD, Merriam AP, Khanna S, et al. (2003) Constitutive properties, not molecular adaptations, mediate extraocular muscle sparing in dystrophic mdx mice. FASEB J 17: 893-895PubMedGoogle Scholar
  32. Porter JD, Merriam AP, Leahy P, et al. (2004) Temporal gene expression profiling of dystrophin-deficient (mdx) mouse diaphragm identifies conserved and muscle group-specific mechanisms in the pathogenesis of muscular dystrophy. Hum Mol Genet 13: 257-269CrossRefPubMedGoogle Scholar
  33. Rouger K, Le Cunff M, Steenman M, et al. (2002) Global/temporal gene expression in diaphragm and hindlimb muscles of dystrophin-deficient (mdx) mice. Am J Physiol Cell Physiol 283: C773-C784PubMedGoogle Scholar
  34. Ryder-Cook AS, Sicinski P, Thomas K, et al. (1988) Localization of the mdx mutation within the mouse dystrophin gene. EMBO J 7: 3017-3021PubMedGoogle Scholar
  35. Sanoudou D, Haslett JN, Kho AT, et al. (2003) Expression profiling reveals altered satellite cell numbers and glycolytic enzyme transcription in nemaline myopathy muscle. Proc Natl Acad Sci U S A 100: 4666-4671CrossRefPubMedGoogle Scholar
  36. Sicinski P, Geng Y, Ryder-Cook AS, et al. (1989) The molecular basis of muscular dystrophy in the mdx mouse: a point mutation. Science 244: 1578-1580PubMedGoogle Scholar
  37. Stedman HH, Sweeney HL, Shrager JB, et al. (1991) The mdx mouse diaphragm reproduces the degenerative changes of Duchenne muscular dystrophy. Nature 352: 536-539CrossRefPubMedGoogle Scholar
  38. Sturn A, Quackenbush J, Trajanoski Z (2002) Genesis: cluster analysis of microarray data. Bioinformatics 18: 207-208CrossRefPubMedGoogle Scholar
  39. Talmadge RJ, Otis JS, Rittler MR, Garcia MD, Spencer SR, et al. (2004) Calcineurin activation influences muscle phenotype in a muscle-specific fashion. BMC Cell Biol 5: 28CrossRefPubMedGoogle Scholar
  40. Tamayo P, Slonim D, Mesirov J, et al. (1999) Interpreting patterns of gene expression with self-organizing maps: methods and application to hematopoietic differentiation. Proc Natl Acad Sci U S A 96: 2907-2912CrossRefPubMedGoogle Scholar
  41. Tkatchenko AV, Le Cam G, Leger JJ, Dechesne CA (2000) Large-scale analysis of differential gene expression in the hindlimb muscles and diaphragm of mdx mouse. Biochim Biophys Acta 1500: 17-30PubMedGoogle Scholar
  42. Tseng BS, Zhao P, Pattison JS, et al. (2002) Regenerated mdx mouse skeletal muscle shows differential mRNA expression. J Appl Physiol 93: 537-545PubMedGoogle Scholar
  43. Yoshida M, Ozawa E (1990) Glycoprotein complex anchoring dystrophin to sarcolemma. Journal of Biochemistry 108: 748-752PubMedGoogle Scholar
  44. Zhao Q, Kho A, Kenney AM, et al. (2002) Identification of genes expressed with temporal-spatial restriction to developing cerebellar neuron precursors by a functional genomic approach. Proc Natl Acad Sci U S A 99: 5704-5709CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Judith N. Haslett
    • 1
  • Peter B. Kang
    • 1
    • 2
  • Mei Han
    • 1
  • Alvin T. Kho
    • 3
  • Despina Sanoudou
    • 1
  • Jay M. Volinski
    • 1
  • Alan H. Beggs
    • 1
  • Isaac S. Kohane
    • 3
    • 4
  • Louis M. Kunkel
    • 1
    • 5
    Email author
  1. 1.Division of Genetics and Genomics ProgramChildren’s Hospital Boston and Harvard Medical SchoolBostonUSA
  2. 2.Department of NeurologyChildren’s Hospital Boston and Harvard Medical SchoolBostonUSA
  3. 3.Informatics ProgramChildren’s Hospital Boston and Harvard Medical SchoolBostonUSA
  4. 4.Division of EndocrinologyChildren’s Hospital Boston and Harvard Medical SchoolBostonUSA
  5. 5.Howard Hughes Medical InstituteChevy ChaseUSA

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