title: Muscle proteomics reveals novel insights into the pathophysiological mechanisms of collagen VI myopathies.
abstract: Mutations in the collagen VI genes cause the Ullrich congenital muscular dystrophy (UCMD), with severe phenotype, and Bethlem myopathy (BM) with mild to moderate phenotype. Both, UCMD and BM patients show dystrophic features with degeneration/regeneration and replacement of muscle with fat and fibrous connective tissue. At molecular level, UCMD patients show autophagic impairment and increased PTP opening; these features are less severe in BM. To elucidate the biochemical mechanisms adopted by the muscle to adapt to collagen VI deficiency in BM and UCMD patients, a proteome analysis was carried out on human muscle biopsies. Qualitative and quantitative differences were assessed by 2D-DIGE coupled to MALDI-ToF/ToF MS. Proteomics results, coupled with immunoblotting, indicate changes in UPR, hexosamine pathway, and amino acid and fatty acid metabolism, suggesting an association of ER stress, metabolic dysregulation, autophagic impairment, and alteration in mechanotransduction signaling. Overall, these results indicate that despite the common downregulation of hexosamine pathway in UCMD and BM, in BM the protein quality control system is sustained by a metabolic adaptation supporting energy requirements for the maintenance of autophagy, counteracting ER misfolded protein overload. In UCMD, this multilayered system may be disrupted and worsened by the metabolic rewiring, which leads to lipotoxicity.
authors.affiliation: Department of Biomedical Sciences for Health, University of Milan , Segrate, Milan 20090, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: De Palma
authors.forename: Daniele
authors.initials: D
authors.lastname: Capitanio
authors.forename: Michele
authors.initials: M
authors.lastname: Vasso
authors.forename: Paola
authors.initials: P
authors.lastname: Braghetta
authors.forename: Chiara
authors.initials: C
authors.lastname: Scotton
authors.forename: Paolo
authors.initials: P
authors.lastname: Bonaldo
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ferlini
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gelfi
mesh_terms: D001706:Biopsy; D016022:Case-Control Studies; D024142:Collagen Type VI / Q000378:metabolism; D003286:Contracture / Q000378:metabolism* / Q000503:physiopathology; D059865:Endoplasmic Reticulum Stress; D005227:Fatty Acids / Q000378:metabolism; D006595:Hexosamines / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000503:physiopathology; D009136:Muscular Dystrophies / Q000151:congenital* / Q000378:metabolism / Q000503:physiopathology; D040901:Proteomics / Q000379:methods*; D015203:Reproducibility of Results; D012598:Sclerosis / Q000378:metabolism* / Q000503:physiopathology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods; D057825:Two-Dimensional Difference Gel Electrophoresis; D056811:Unfolded Protein Response
chemical_list: D024142:Collagen Type VI; D005227:Fatty Acids; D006595:Hexosamines
keywords: 2D-DIGE; Bethlem myopathy; Collagen VI; Ullrich congenital muscular dystrophy; alpha-ketoglutarate; endoplasmic reticulum; hexosamine; unfolded protein response