Steroids in Duchenne muscular dystrophy: from clinical trials to genomic research
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.
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Intermittent PTH treatment improves bone and muscle in glucocorticoid treated Mdx mice: A model of Duchenne Muscular Dystrophy
2019, BoneCitation Excerpt :In addition, the significant reduction in type 2c fibers suggests that Mdx muscle has a limited capacity to differentiate muscle properly, and that glucocorticoids, PTH, and co-treatments aid in myocyte differentiation. It has been suggested that glucocorticoids may improve myogenic precursor cells or myoblast proliferation, as well as myotube formation in Mdx mice, helping to offset the typical effect of glucocorticoids to increase muscle atrophy, resulting in a net increase in muscle regeneration and growth in mdx mice [38–41]. The important role of PTH in myocyte differentiation has been suggested [37], but the interaction between glucocorticoids and PTH as seen here in decreased expression of Spp1 (osteopontin) and decreased fibers with central nuclei in Mdx muscle needs further investigation.
Liposomal steroid nano-drug is superior to steroids as-is in mdx mouse model of Duchenne muscular dystrophy
2019, Nanomedicine: Nanotechnology, Biology, and MedicineDebio-025 is more effective than prednisone in reducing muscular pathology in mdx mice
2010, Neuromuscular DisordersCitation Excerpt :Thus, non-immunosuppressant analogs of CsA that do not inhibit calcineurin, such as Debio-025, are likely to be far more effective in treating muscular dystrophy. The corticosteroids prednisone or deflazacort are currently the standard of care for treatment of Duchenne muscular dystrophy, which appear to prolong muscle strength and have other minor benefits in reducing disease severity [25–27]. However, corticosteroids cause excessive weight gain, stunted growth, cataracts, osteoporosis, and hypertension [25–28].
Inhibition of prostaglandin D synthase suppresses muscular necrosis
2009, American Journal of PathologyRegenerative pharmacology in the treatment of genetic diseases: The paradigm of muscular dystrophy
2009, International Journal of Biochemistry and Cell BiologyEffect of deflazacort on cardiac and sternocleidomastoid muscles in Duchenne muscular dystrophy: A magnetic resonance imaging study
2009, European Journal of Paediatric NeurologyCitation Excerpt :Various possibilities have been proposed based mainly on observations in mouse models of muscular dystrophy and on a limited number of patients’ studies.8 These possibilities include (1) alteration of the mRNA levels of structural, signaling, and immune response genes9; (2) reduction of cytotoxic T lymphocytes10,11; (3) lowering of calcium influx and concentration12,13; (4) an increase of laminin expression and myogenic repair14; (5) retardation of muscle apoptosis and cellular infiltration15; (6) enhancement of dystrophin expression16; (7) an effect on neuromuscular transmission17; (8) protection against mechanically induced fiber damage18; (9) attenuation of muscle fiber necrosis19; (10) slowing of the rate of skeletal muscle breakdown20–22; and (11) an increase of muscle levels of taurine and creatine.23 More studies are necessary to establish the precise cellular mechanisms by which corticosteroids produce their beneficial effects in DMD.