Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies
| Autor: | Tania Tiepolo, Nadir M. Maraldi, Patrizia Sabatelli, Paolo Bernardi, Luciano Merlini, Paolo Bonaldo, Paola Braghetta, Alessandra Ferlini, Alessandra Zamparelli, Alessia Angelin |
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| Přispěvatelé: | Merlini L, Angelin A, Tiepolo T, Braghetta P, Sabatelli P, Zamparelli A, Ferlini A, Maraldi NM, Bonaldo P, Bernardi P. |
| Rok vydání: | 2008 |
| Předmět: |
Mitochondria
Muscular dystrophy Apoptosis Adult Pathology medicine.medical_specialty mitochondria muscular dystrophy Ullrich congenital muscular dystrophy Biopsy Collagen Type VI Biology Mice Muscular Diseases Collagen VI Cyclosporin a medicine Animals Humans Myocyte Child Mice Knockout Multidisciplinary Bethlem myopathy Skeletal muscle Anatomy Biological Sciences Middle Aged medicine.disease medicine.anatomical_structure Cyclosporine ITGA7 |
| Zdroj: | Proceedings of the National Academy of Sciences. 105:5225-5229 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.0800962105 |
| Popis: | Ullrich congenital muscular dystrophy and Bethlem myopathy are skeletal muscle diseases that are due to mutations in the genes encoding collagen VI, an extracellular matrix protein forming a microfibrillar network that is particularly prominent in the endomysium of skeletal muscle. Myoblasts from patients affected by Ullrich congenital muscular dystrophy display functional and ultrastructural mitochondrial alterations and increased apoptosis due to inappropriate opening of the permeability transition pore, a mitochondrial inner membrane channel. These alterations could be normalized by treatment with cyclosporin A, a widely used immunosuppressant that desensitizes the permeability transition pore independently of calcineurin inhibition. Here, we report the results of an open pilot trial with cyclosporin A in five patients with collagen VI myopathies. Before treatment, all patients displayed mitochondrial dysfunction and increased frequency of apoptosis, as determined in muscle biopsies. Both of these pathologic signs were largely normalized after 1 month of oral cyclosporin A administration, which also increased muscle regeneration. These findings demonstrate that collagen VI myopathies can be effectively treated with drugs acting on the pathogenic mechanism downstream of the genetic lesion, and they represent an important proof of principle for the potential therapy of genetic diseases. |
| Databáze: | OpenAIRE |
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