Low-protein diet to correct defective autophagy in patients with collagen VI related myopathies

Muscular dystrophies are genetic, progressive diseases for which no cure is yet available. We have discovered why muscle fibers degenerate in two human muscular dystrophies caused by abnormalities of Collagen VI, Ullrich Congenital Muscular Dystrophy (UCMD) and Bethlem Myopathy (BM). The absence of Collagen VI has a major impact inside the fibers resulting in structural and functional abnormality of mitochondria and excessive cell death. The trigger is a protracted opening of a mitochondrial channel called the “Permeability Transition Pore” (PTP), which can be inhibited by the drug cyclosporin A (CsA). A short-term pilot trial with CsA in BM/UCMD patients showed correction of the mitochondrial dysfunction, while a long-term use of CsA improved muscle strength in the limbs but not in the respiratory muscles of UCMD patients. We have subsequently shown that "autophagy", the mechanism by which the cells "self-digest" intracellular damaged proteins and abnormal mitochondria, is defective both in the animal model and in patients. The defective autophagy impairs removal of altered mitochondria, amplifies the defect and worsens the damage. In the mouse model a low-protein diet showed reactivation of autophagy, cleared defective mitochondria and led to normalization of force in muscle. Even cyclosporine A, the mitochondrial PTP inhibitor, reactivated autophagy in the mouse model, hinting at a common target among all beneficial treatments – namely autophagy. Our project aims to evaluate the efficacy and safety of a normocaloric low-protein diet (LPD) in adult BM/UCMD patients. A LPD will be given for 1 year and reactivation of autophagy will be evaluated as the change of Beclin 1, a marker of autophagy, in muscle biopsy. Further aims of the project are the search for non–invasive biomarkers signaling reactivation of autophagy and the validation of a comprehensive combination of novel approaches to evaluate the nutritional status in patients and its changes with the LPD.