Autophagy activation in COL6 myopathic patients by a low-protein-diet pilot trial



Castagnaro S(1), Pellegrini C(2), Pellegrini M(3), Chrisam M(1), Sabatelli
P(2,)(4), Toni S(3), Grumati P(5), Ripamonti C(6), Pratelli L(7), Maraldi
NM(2,)(4), Cocchi D(8), Righi V(9), Faldini C(10), Sandri M(11,)(12), Bonaldo
P(1,)(13), Merlini L(2).

Author information:
(1)a Department of Molecular Medicine , University of Padova , Padova , Italy.
(2)b Laboratory of Musculoskeletal Cell Biology , Rizzoli Orthopedic Institute ,
Bologna , Italy. (3)c Department of Diagnostic , Clinical and Public Health
Medicine, University of Modena and Reggio Emilia , Modena , Italy. (4)d Institute
of Molecular Genetics, CNR National Research Council of Italy, Rizzoli Orthopedic
Institute , Bologna , Italy. (5)e Institute of Biochemistry II, Goethe University
School of Medicine , Frankfurt am Main , Germany. (6)f Department of Medicine and
Rheumatology , University of Bologna , Bologna , Italy. (7)g Clinical Pathology
Unit, Rizzoli Orthopedic Institute , Bologna , Italy. (8)h Department of
Statistical Sciences , University of Bologna , Bologna , Italy. (9)i Department
of Life Quality Studies , Campus Rimini , University of Bologna , Bologna ,
Italy. (10)j Department of Orthopedics , University of Bologna , Bologna , Italy.
(11)k Department of Biomedical Sciences , University of Padova , Padova , Italy.
(12)l Venetian Institute of Molecular Medicine , Padova , Italy. (13)m CRIBI
Biotechnology Center, University of Padova , Padova , Italy.

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 months 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 year 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 non-invasive tool for monitoring autophagy activation
in patients.

DOI: 10.1080/15548627.2016.1231279
PMID: 27656840 [PubMed – as supplied by publisher

FONTE: Pubmed