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.