Collagen VI Myopathies Research Articles

Collagen VI myopathies: From the animal model to the clinical trial

Collagen VI myopathies: From the animal model to the clinical trial

Dysfunction of Mitochondria and Sarcoplasmic Reticulum in the Pathogenesis of Collagen VI Muscular Dystrophies

Ullrich Congenital Muscular Dystrophy (UCMD) and Bethlem Myopathy (BM) are muscle diseases due to mutations in the genes encoding the extracellular matrix protein collagen VI. Generation of a dystrophic mouse model where collagen VI synthesis was prevented by genetic ablation of the Col6a1 gene allowed an investigation of pathogenesis, which revealed the existence of a Ca(2+)-mediated dysfunction of mitochondria and the sarcoplasmic reticulum. A key event appears to be inappropriate opening of the mitochondrial permeability transition pore, an inner membrane high-conductance channel. Consistently, the Col6a1(-/-) myopathic mice could be cured with cyclosporin A through inhibition of cyclophilin D, a matrix protein that sensitizes the pore to opening. Studies of myoblasts from UCMD and BM patients demonstrated the existence of a latent mitochondrial dysfunction irrespective of the genetic lesion responsible for the lack or the alteration of collagen VI. These studies suggest that PTP opening may represent the final common pathway for skeletal muscle fiber death; and provided a rationale for a pilot clinical trial with cyclosporin A in patients affected by UCMD and BM, a study that holds great promise for the future treatment of collagen VI myopathies.

Therapy of Collagen VI-Related Myopathies (Bethlem and Ullrich)

The collagen VI-related myopathies comprise two major forms, Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD), which show a variable combination of muscle wasting and weakness, joint contractures, distal laxity, and respiratory compromise. Specific diagnosis requires molecular genetic testing showing mutation in one of the three genes involved. This review summarizes current treatments, in particular indication for physiotherapy, orthopedic treatment for correction of foot deformity, scoliosis, and flexion contractures of elbows, and treatment of respiratory failure. The turning point in basic research on collagen VI myopathies was the discovery of an unexpected mitochondrial dysfunction as a pathogenetic mechanism underlying the myopathic syndrome seen in Col6a1 null mice. Treatment of Col6a1(-/-) mice with cyclosporin A (CsA) rescued the mitochondrial dysfunction and decreased apoptosis. Similar mitochondrial defects were revealed in cultures of UCMD patients. The results of an open pilot trial with CsA in five patients with collagen VI-related myopathies are summarized and discussed. With the availability of new potential effective treatments, several challenges must be addressed in conducting trials in orphan diseases and in neuromuscular disorders in particular. Outcome measures are discussed in the context of the expected effect of the cure. Randomized clinical trials often are not feasible for rare diseases, and sometimes would be ethically inappropriate. The need to develop alternative outcome measures or biomarkers using platforms such as genomics and proteomics is stressed in this context.

Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies.

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.

Ehlers–Danlos syndrome due to tenascin‐X deficiency: Muscle weakness and contractures support overlap with collagen VI myopathies

American Journal of Medical Genetics Part AVolume 143A, Issue 18 p. 2215-2219 Correspondence Ehlers–Danlos syndrome due to tenascin-X deficiency: Muscle weakness and contractures support overlap with collagen VI myopathies† N.C. Voermans, Corresponding Author N.C. Voermans n.voermans@neuro.umcn.nl Neuromuscular Centre Nijmegen, Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, The NetherlandsNeuromuscular Centre Nijmegen, Department of Neurology, 935, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.Search for more papers by this authorG.J. Jenniskens, G.J. Jenniskens Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The NetherlandsSearch for more papers by this authorB.C. Hamel, B.C. Hamel Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The NetherlandsSearch for more papers by this authorJ. Schalkwijk, J. Schalkwijk Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen, The NetherlandsSearch for more papers by this authorP. Guicheney, P. Guicheney Inserm, U582, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France Université Pierre et Marie Curie-Paris 6, UMR S582, IFR14 Paris, FranceSearch for more papers by this authorB.G. van Engelen, B.G. van Engelen Neuromuscular Centre Nijmegen, Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, The NetherlandsSearch for more papers by this author N.C. Voermans, Corresponding Author N.C. Voermans n.voermans@neuro.umcn.nl Neuromuscular Centre Nijmegen, Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, The NetherlandsNeuromuscular Centre Nijmegen, Department of Neurology, 935, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.Search for more papers by this authorG.J. Jenniskens, G.J. Jenniskens Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The NetherlandsSearch for more papers by this authorB.C. Hamel, B.C. Hamel Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The NetherlandsSearch for more papers by this authorJ. Schalkwijk, J. Schalkwijk Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen, The NetherlandsSearch for more papers by this authorP. Guicheney, P. Guicheney Inserm, U582, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France Université Pierre et Marie Curie-Paris 6, UMR S582, IFR14 Paris, FranceSearch for more papers by this authorB.G. van Engelen, B.G. van Engelen Neuromuscular Centre Nijmegen, Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, The NetherlandsSearch for more papers by this author First published: 17 August 2007 https://doi.org/10.1002/ajmg.a.31899Citations: 36 † How to cite this article: Voermans NC, Jenniskens GJ, Hamel BC, Schalkwijk J, Guicheney P, van Engelen BG. 2007. Ehlers–Danlos syndrome due to tenascin-X deficiency: Muscle weakness and contractures support overlap with collagen VI myopathies. Am J Med Genet Part A 143A:2215–2219. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume143A, Issue1815 September 2007Pages 2215-2219 RelatedInformation

Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency.

Collagen VI is an extracellular matrix protein that forms a microfilamentous network in skeletal muscles and other organs. Inherited mutations in genes encoding collagen VI in humans cause two muscle diseases, Bethlem myopathy and Ullrich congenital muscular dystrophy. We previously generated collagen VI-deficient (Col6a1-/-) mice and showed that they have a muscle phenotype that strongly resembles Bethlem myopathy. The pathophysiological defects and mechanisms leading to the myopathic disorder were not known. Here we show that Col6a1-/- muscles have a loss of contractile strength associated with ultrastructural alterations of sarcoplasmic reticulum (SR) and mitochondria and spontaneous apoptosis. We found a latent mitochondrial dysfunction in myofibers of Col6a1-/- mice on incubation with the selective F1F(O)-ATPase inhibitor oligomycin, which caused mitochondrial depolarization, Ca2+ deregulation and increased apoptosis. These defects were reversible, as they could be normalized by plating Col6a1-/- myofibers on collagen VI or by addition of cyclosporin A (CsA), the inhibitor of mitochondrial permeability transition pore (PTP). Treatment of Col6a1-/- mice with CsA rescued the muscle ultrastructural defects and markedly decreased the number of apoptotic nuclei in vivo. These findings indicate that collagen VI myopathies have an unexpected mitochondrial pathogenesis that could be exploited for therapeutic intervention.