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

TLDR

Collagen VI myopathies, including Ullrich congenital muscular dystrophy and Bethlem myopathy, arise from collagen VI mutations and are characterized by mitochondrial dysfunction and apoptosis driven by permeability transition pore opening. This study reports an open pilot trial of cyclosporin A in five patients with collagen VI myopathies. Cyclosporin A, an immunosuppressant that desensitizes the permeability transition pore independently of calcineurin inhibition, was used to normalize these mitochondrial alterations. One month of oral cyclosporin A largely restored mitochondrial function and reduced apoptosis, increased muscle regeneration, and demonstrated that targeting downstream mechanisms can effectively treat 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.