NMR EVALUATION OF MITOCHONDRIAL DYSFUNCTION IN LOW-PROTEIN DIET IN COLLAGEN VI-RELATED MYOPATHIES

A pilot clinical trial based on nutritional modulation was designed to assess the efficacy of one-year low-protein diet (LPD) in activating autophagy in skeletal muscle of patients affected by COL6/collagen VI-related myopathies. Ullrich congenital muscular dystrophy and Bethlem myopathy are rare inherited muscle disorders caused by mutations of COL6 genes and for which no cure is available yet. Studies in COL6 null mice revealed that myofiber degeneration involves autophagy defects and that forced activation of autophagy results in the amelioration of muscle pathology. Seven adult patients affected by COL6 myopathies underwent a controlled low-protein diet for twelve months and the alterated metabolites pathway was evaluated in blood samples. Safety measures were assessed, including muscle strength, motor and respiratory function, and metabolic parameters. The treatment resulted safe as shown by preservation of lean-fat percentage of body composition, muscle strength and function. Patients displayed a reduction in lactate (ranging from 10% to 60%) and a decrease in acetate serum levels after one year, as revealed by NMR analysis. The reduced concentration of lactate and acetate after LPD suggests an improvement in mitochondrial aerobic energy production through the tricarboxylic acid cycle, with a reduced conversion of pyruvate to lactate. These metabolic changes point to an improved mitochondrial function. The data provide evidence that LPD is able to activate autophagy and is safe and tolerable in patients with COL6 myopathies, indicating autophagy activation as a potential target for therapeutic applications.