aneuploidy and polyploidy in germ line cells of the male chinese hamster cricetulus griseus

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STABILITY OF ABNORMAL KARYOTYPES IN CELL CULTURE1

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Collagen VI myopathies: pathogenic mechanism and therapeutic strategies

Collagen (Col) VI is a major component of the extracellular matrix which, in skeletal muscle, is localized just outside the basement membrane. Deficiency of ColVI in humans due to mutations of COL6 genes gives rise to Bethlem Myopathy (BM), Ullrich Congenital Muscular Dystrophy (UCMD), and Myosclerosis Myopathy. About 70 different COL6 gene  mutations have been associated to ColVI myopathies which, although present  a wide range of clinical features, share a common pathogenesis. This mechanism, initially identified in the Col6a1-/- model (Irwin et al., 2003), and then in cultures from BM and UCMD patients (Angelin et al., 2007), involves a mitochondrial dysfunction due to deregulation of the permeability transition pore (PTP). The pat hogenic role of PTP opening, causing the release of proapoptotic factors, has been confirmed by the normalizing effect of cyclosporine A (CsA) on  the mitochondrial defect and on the increased apoptotic rate in both the mouse model and in a selected group of patients (Merlini et al., 2008). We have recently demonstrated that the persistence of abnormal mitochondria and apoptosis are amplified by defective autophagy (Grumati et al., 2010). In fact, forced activation of autophagy by genetic, dietary and pharmacological approaches restore myofiber survival and ameliorate the dystrophic phenotype in mice. Since also muscle cells of BM and UCMD patients  present a defective activation of the autophagic machinery, it will be possible to restore this activity by using  a low protein diet or drugs capable to reactivate autophagy. To monitor the effects of therapies on ColVI-related myopathies highly invasive muscle/skin biopsies have been so far utilized. We have recently obtained evidence that ColVI expression in blood macrophages from BM and UCMD patients can be detected at levels comparable to those observed in muscle biopsies and cultured skin fibroblasts (Gualandi et al., 2011). These data support the suitability of peripheral blood macrophages as a reliable, minimally invasive tool for supplementing or replacing highly invasive biopsies in the diagnosis and monitoring of ColVI myopathies. 1. Irwin WA et al., Nat Genet 2003;35:267-71 2. Angelin A et al., PNAS USA 2007;104:991-6 3. Merlini L et al., PNAS USA 2008;105:5225-9 4. Gualandi F et al., Muscle Nerve 2011;44:80-

Autophagy is defective in collagen VI muscular dystrophies and its reactivation rescues myofiber degeneration

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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