Elsevier

Neuromuscular Disorders

Volume 12, Supplement, October 2002, Pages S162-S165
Neuromuscular Disorders

Steroids in Duchenne muscular dystrophy: from clinical trials to genomic research

https://doi.org/10.1016/S0960-8966(02)00101-3Get rights and content

Abstract

Steroids represent the only pharmacological palliative treatment for Duchenne muscular dystrophy. However, they do have side effects and despite a large number of published studies showing their efficacy, they are still not universally used. This is largely due to the lack of functional outcome and quality of life measures in most of the published studies and suggests that further trials might be required to answer some of the still unclear aspects of their role. Another important aspect of steroid therapy in Duchenne dystrophy is that we do not know how they work in dystrophic muscle. We have initiated a collaborative study on gene profiling using microarray in steroid-treated mdx mice. cDNA microarray studies were performed to examine the levels of skeletal muscle gene expression in a pool of mdx mice treated with prednisolone for 1 and 6 weeks. Interesting preliminary data on untreated mdx mice suggest that the gene profiling of young (7 weeks) versus older (12 weeks) mice is very significantly different. Furthermore, a large number of genes showed significant changes in expression at the mRNA level on treatment with prednisolone. These included structural protein genes; signalling genes and genes involved in immune response. Hopefully, analysis of this pattern of steroid-induced gene expression will provide some insight into understanding how glucocorticoids improve strength in Duchenne dystrophy, and may help in developing more effective and less toxic therapeutic approaches.

Section snippets

Duchenne muscular dystrophy and steroids: clinical trials

Duchenne muscular dystrophy is a common and progressive form of muscular dystrophy for which no curative treatment is available. Corticosteroid therapy has been shown by a number of studies to have some positive effect on Duchenne dystrophy: at least 16 studies on nearly 1000 affected children have been published in the last three decades (reviewed in Ref. [1]). Most studies have demonstrated transitory improvement and/or stabilization of muscle strength, but the trials were relatively

Mechanism of action of steroids in skeletal muscle

The mechanism of action of steroids in Duchenne muscular dystrophy is not known, but a number of theories have been put forward. These include:

  • (a)

    positive effect of steroids on myogenesis [9], [10];

  • (b)

    anabolic effect on muscle, resulting in increased muscle mass [11];

  • (c)

    stabilization of muscle fibre membranes [12];

  • (d)

    attenuation of muscle necrosis [13], although this is controversial [14], [15];

  • (e)

    effect on intracellular calcium concentrations [16], [17];

  • (f)

    immunosuppressive effect with reduction of

Acknowledgements

This work was funded by the Duchenne Parent Support Group of the Netherlands. The author wishes to thank Ivan Fisher, David Abraham and Jennifer Morgan for the collaboration on the gene profiling project. The author also wishes to thank the Muscular Dystrophy Campaign for the support provided in establishing the network of the 15 UK clinical centres involved in the project: Steroids in DMD, and Dr Adnan Manzur for the helpful discussion related to the planned steroid trial.

References (25)

  • G.M. Fenichel et al.

    Long-term benefit from prednisone therapy in Duchenne muscular dystrophy

    Neurology

    (1877)
  • V. Guerriero et al.

    Dexamethasone effects on myoblast proliferation and differentiation

    Endocrinology

    (1980)
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