Muscle proteomics reveals novel insights into the pathophysiological mechanisms of collagen vi myopathies

Sara De Palma, Daniele Capitanio, Michele Vasso, Paola Braghetta, Chiara Scotton, Paolo Bonaldo, Hanns Lochmüller, Francesco Muntoni, Alessandra Ferlini, Cecilia Gelfi

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)5022-5030
Number of pages9
JournalJournal of Proteome Research
Issue number11
Publication statusPublished - Nov 7 2014


  • 2D-DIGE
  • alpha-ketoglutarate
  • Bethlem myopathy
  • Collagen VI
  • endoplasmic reticulum
  • hexosamine
  • Ullrich congenital muscular dystrophy
  • unfolded protein response

ASJC Scopus subject areas

  • Biochemistry
  • Chemistry(all)
  • Medicine(all)


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