Prednisone reduces muscle degeneration in dystrophin-deficient Caenorhabditis elegans

Duchenne muscular dystrophy is a degenerative muscular disease caused by mutations in the dystrophin gene. There is no curative treatment against Duchenne muscular dystrophy. In several countries, the steroid prednisone (or analogs) is prescribed as a palliative treatment. In the model animal Caenorhabditis elegans, mutations of the dys-1 dystrophin-like gene lead to a muscular degenerative phenotype when they are associated with a mild MyoD mutation. This cheap and fast-growing model of dystrophinopathy may be used to screen for molecules able to slow muscle degeneration. In a blind screen of approximately 100 compounds covering a wide spectrum of targets, we found that prednisone is beneficial to the C. elegans dystrophin-deficient muscles. Prednisone reduces by 40% the number of degenerating cells in this animal. This result is a proof-of-principle for the use of C. elegans as a tool in the search for molecules active against the effects of dystrophin-deficiency. Moreover, since C. elegans is not susceptible to inflammation, this suggests that prednisone exerts a direct effect on muscle survival.

[1]  L. Ségalat,et al.  Mutations in the Caenorhabditis elegans dystrophin-like gene dys-1 lead to hyperactivity and suggest a link with cholinergic transmission , 1998, Neurogenetics.

[2]  L. Kunkel,et al.  The structural and functional diversity of dystrophin , 1993, Nature Genetics.

[3]  K. Davies,et al.  The role of utrophin in the potential therapy of Duchenne muscular dystrophy , 2002, Neuromuscular Disorders.

[4]  V. Dubowitz What Is Muscular Dystrophy? Forty Years of Progressive Ignorance , 2000, Journal of the Royal College of Physicians of London.

[5]  C. Johnson,et al.  Genetic pharmacology: interactions between drugs and gene products in Caenorhabditis elegans. , 1995, Methods in cell biology.

[6]  L. Ségalat,et al.  Genetic evidence for a dystrophin-glycoprotein complex (DGC) in Caenorhabditis elegans. , 2002, Gene.

[7]  L. Metzinger,et al.  Modulation by prednisolone of calcium handling in skeletal muscle cells , 1995, British Journal of Pharmacology.

[8]  S. Brenner The genetics of Caenorhabditis elegans. , 1974, Genetics.

[9]  A. Briguet,et al.  Transcriptional activation of the utrophin promoter B by a constitutively active Ets-transcription factor , 2003, Neuromuscular Disorders.

[10]  R. Waterston,et al.  Dominant mutations affecting muscle structure in Caenorhabditis elegans that map near the actin gene cluster. , 1984, Journal of molecular biology.

[11]  L. Kunkel,et al.  Dystrophin and muscular dystrophy: past, present, and future. , 2001, Molecular genetics and metabolism.

[12]  U. Rüegg,et al.  Calcium influx inhibition by steroids and analogs in C2C12 skeletal muscle cells , 1998, British journal of pharmacology.

[13]  L. Ségalat,et al.  Muscular degeneration in the absence of dystrophin is a calcium-dependent process , 2001, Current Biology.

[14]  L. Ségalat,et al.  Genetic suppression of phenotypes arising from mutations in dystrophin-related genes in Caenorhabditis elegans , 2000, Current Biology.

[15]  L. Ségalat,et al.  Overexpression of dystrobrevin delays locomotion defects and muscle degeneration in a dystrophin-deficient Caenorhabditis elegans , 2002, Neuromuscular Disorders.

[16]  B. Wong,et al.  Corticosteroids in Duchenne Muscular Dystrophy: A Reappraisal , 2002, Journal of child neurology.

[17]  M. Koenig,et al.  Complete cloning of the duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals , 1987, Cell.

[18]  M. Bobrow,et al.  Dystrophins in vertebrates and invertebrates. , 1998, Human molecular genetics.