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

Abstract

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. mitochondria ͉ muscular dystrophy

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

“…This study 33 shows that treatment with moderate doses of CsA favorably affects mitochondrial function in collagen VI myopathies in vivo, and dramatically decreases the frequency of muscle cell death in the patients. Whether this will eventually stop progression of the disease or translate into a better muscle performance depends on multiple factors, such as muscle loss and extent of fibrosis at the time of treatment, and potential for muscle regeneration in individual patients.…”

“…It is quite encouraging that CsA decreased apoptosis in all treated patients within 1 month, 33 because this finding suggests that assessing the effects of CsA on the clinical course of the disease may be feasible in future clinical trials. Some reason for hope also comes from the observation that treatment with CsA increased muscle regeneration.…”

“…33 In addition, unlike samples from normal donors, in which apoptosis was undetectable, all samples from patients had a sizeable number of apoptotic nuclei in the first biopsy, and treatment with CsA considerably decreased the occurrence of apoptosis in all patients, indicating a cause-and-effect relationship be-…”

“…33 Four were affected by UCMD and one by BM; three were of pediatric age and two were adults. Their collagen VI ranged from almost normal to marked depletion, and the pathogenic mutation involved each of the three COL6 genes.…”

Sarcolemmal Specific Collagen VI Deficient Myopathy in a Labrador Retriever

“…A long‐term evaluation of CsA treatment in 6 children treated for 1–3 years with maintenance doses of CsA between 1.25 and 3 mg/kg q24 h showed a significant increase in muscle strength without changes in muscle function or effects on the progressive deterioration of respiratory function 17. The efficacy of CsA in this dog could not be evaluated owing to the limited duration of the treatment and lack of objective measurements in muscle strength.…”