title: Autophagy activation in COL6 myopathic patients by a low-protein-diet pilot trial.
abstract: A pilot clinical trial based on nutritional modulation was designed to assess the efficacy of a one-year low-protein diet 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 yet available. 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 12 mo and we evaluated the presence of autophagosomes and the mRNA and protein levels for BECN1/Beclin 1 and MAP1LC3B/LC3B in muscle biopsies and blood leukocytes. Safety measures were assessed, including muscle strength, motor and respiratory function, and metabolic parameters. After one y of low-protein diet, autophagic markers were increased in skeletal muscle and blood leukocytes of patients. The treatment was safe as shown by preservation of lean:fat percentage of body composition, muscle strength and function. Moreover, the decreased incidence of myofiber apoptosis indicated benefits in muscle homeostasis, and the metabolic changes pointed at improved mitochondrial function. These data provide evidence that a low-protein diet is able to activate autophagy and is safe and tolerable in patients with COL6 myopathies, pointing at autophagy activation as a potential target for therapeutic applications. In addition, our findings indicate that blood leukocytes are a promising noninvasive tool for monitoring autophagy activation in patients.
authors.affiliation: a Department of Molecular Medicine , University of Padova , Padova , Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Castagnaro
authors.affiliation: b Laboratory of Musculoskeletal Cell Biology, Rizzoli Orthopedic Institute , Bologna , Italy.
authors.forename: Camilla
authors.initials: C
authors.lastname: Pellegrini
authors.affiliation: c Department of Diagnostic , Clinical and Public Health Medicine, University of Modena and Reggio Emilia , Modena , Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Pellegrini
authors.affiliation: a Department of Molecular Medicine , University of Padova , Padova , Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Chrisam
authors.affiliation: b Laboratory of Musculoskeletal Cell Biology, Rizzoli Orthopedic Institute , Bologna , Italy.|d Institute of Molecular Genetics, CNR National Research Council of Italy, Rizzoli Orthopedic Institute , Bologna , Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Sabatelli
authors.affiliation: c Department of Diagnostic , Clinical and Public Health Medicine, University of Modena and Reggio Emilia , Modena , Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Toni
authors.affiliation: e Institute of Biochemistry II, Goethe University School of Medicine , Frankfurt am Main , Germany.
authors.forename: Paolo
authors.initials: P
authors.lastname: Grumati
authors.affiliation: f Department of Medicine and Rheumatology , University of Bologna , Bologna , Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Ripamonti
authors.affiliation: g Clinical Pathology Unit, Rizzoli Orthopedic Institute , Bologna , Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Pratelli
authors.affiliation: b Laboratory of Musculoskeletal Cell Biology, Rizzoli Orthopedic Institute , Bologna , Italy.|d Institute of Molecular Genetics, CNR National Research Council of Italy, Rizzoli Orthopedic Institute , Bologna , Italy.
authors.forename: Nadir M
authors.initials: NM
authors.lastname: Maraldi
authors.affiliation: h Department of Statistical Sciences , University of Bologna , Bologna , Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cocchi
authors.affiliation: i Department of Life Quality Studies , Campus Rimini, University of Bologna , Bologna , Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Righi
authors.affiliation: j Department of Orthopedics , University of Bologna , Bologna , Italy.
authors.forename: Cesare
authors.initials: C
authors.lastname: Faldini
authors.affiliation: k Department of Biomedical Sciences , University of Padova , Padova , Italy.|l Venetian Institute of Molecular Medicine , Padova , Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Sandri
authors.affiliation: a Department of Molecular Medicine , University of Padova , Padova , Italy.|m CRIBI Biotechnology Center, University of Padova , Padova , Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bonaldo
authors.affiliation: b Laboratory of Musculoskeletal Cell Biology, Rizzoli Orthopedic Institute , Bologna , Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Merlini
mesh_terms: D000328:Adult; D000409:Alanine / Q000378:metabolism; D001343:Autophagy; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D001823:Body Composition; D024142:Collagen Type VI / Q000235:genetics*; D003286:Contracture / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018753:Diet, Protein-Restricted; D005260:Female; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D009132:Muscles / Q000473:pathology; D009135:Muscular Diseases / Q000178:diet therapy* / Q000378:metabolism / Q000503:physiopathology; D009136:Muscular Dystrophies / Q000151:congenital / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010865:Pilot Projects; D012598:Sclerosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016138:Walking; D055815:Young Adult
chemical_list: D015415:Biomarkers; D024142:Collagen Type VI; D019344:Lactic Acid; D000409:Alanine
keywords: Bethlem myopathy; Ullrich congenital muscular dystrophy; autophagy; clinical trial; collagen VI; low-protein diet; muscular dystrophies