A Multidisciplinary Evaluation of the Effectiveness of Cyclosporine A in Dystrophic Mdx Mice

• Published in: The American journal of pathology Vol. 166; no. 2; pp. 477 - 489
• Main Authors: De Luca, Annamaria, Nico, Beatrice, Liantonio, Antonella, Didonna, Maria Paola, Fraysse, Bodvael, Pierno, Sabata, Burdi, Rosa, Mangieri, Domenica, Rolland, Jean-François, Camerino, Claudia, Zallone, Alberta, Confalonieri, Paolo, Andreetta, Francesca, Arnoldi, Elisa, Courdier-Fruh, Isabelle, Magyar, Josef P., Frigeri, Antonio, Pisoni, Michela, Svelto, Maria, Conte Camerino, Diana
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.02.2005; ASIP; American Society for Investigative Pathology
• Subjects: Animals; Biological and medical sciences; Body Weight - drug effects; Calcium - metabolism; Chlorides - metabolism; Coloring Agents - pharmacology; Creatine Kinase - blood; Cyclosporine - pharmacology; Electrophysiology; Fibrosis; Fura-2 - pharmacology; Immunohistochemistry; Immunosuppressive Agents - pharmacology; Investigative techniques, diagnostic techniques (general aspects); Ions; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Inbred mdx; Muscle, Skeletal - drug effects; Muscles - drug effects; Muscular Dystrophies - drug therapy; Original Research Paper; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Physical Conditioning, Animal; Spectrophotometry; Time Factors; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta1; Evaluation; Vertebrata; Anatomic pathology; Mammalia; Mouse; Efficiency; Animal; Rodentia; Ciclosporin; Dystrophy; Immunosuppressive agent; Multidisciplinary
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/S0002-9440(10)62270-5

Chronic inflammation is a secondary reaction of Duchenne muscular dystrophy and may contribute to disease progression. To examine whether immunosuppressant therapies could benefit dystrophic patients, we analyzed the effects of cyclosporine A (CsA) on a dystrophic mouse model. Mdx mice were treated with 10 mg/kg of CsA for 4 to 8 weeks throughout a period of exercise on treadmill, a protocol that worsens the dystrophic condition. The CsA treatment fully prevented the 60% drop of forelimb strength induced by exercise. A significant amelioration ( P < 0.05) was observed in histological profile of CsA-treated gastrocnemius muscle with reductions of nonmuscle area (20%), centronucleated fibers (12%), and degenerating area (50%) compared to untreated exercised mdx mice. Consequently, the percentage of normal fibers increased from 26 to 35% in CsA-treated mice. Decreases in creatine kinase and markers of fibrosis were also observed. By electrophysiological recordings ex vivo , we found that CsA counteracted the decrease in chloride conductance (gCl), a functional index of degeneration in diaphragm and extensor digitorum longus muscle fibers. However, electrophysiology and fura-2 calcium imaging did not show any amelioration of calcium homeostasis in extensor digitorum longus muscle fibers. No significant effect was observed on utrophin levels in diaphragm muscle. Our data show that the CsA treatment significantly normalized many functional, histological, and biochemical endpoints by acting on events that are independent or downstream of calcium homeostasis. The beneficial effect of CsA may involve different targets, reinforcing the usefulness of immunosuppressant drugs in muscular dystrophy.