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.
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ER stress is a mechanism involved in the pathogenesis of a range of systemic diseases including connective tissue disorders.
“increasing observations indicate ER stress as a mechanism involved in the pathogenesis of a range of systemic diseases including connective tissue disorders [56–59]”
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- Authors
- De Palma, S., Capitanio, D., Vasso, M., Braghetta, P., Scotton, C., Bonaldo, P., Lochmüller, H., Muntoni, F., Ferlini, A., & Gelfi, C.
- Affiliations
- Department of Biomedical Sciences for Health, University of Milan, Segrate, Milan 20090, Italy
- University of Milan (IT)
- Institute of Molecular Bioimaging and Physiology (IT)
- University of Padua (IT)
- University of Ferrara (IT)
- Newcastle University (GB)
- Dubowitz Neuromuscular Centre, University College London, Institute of Child Health, London WC1N 1EH, United Kingdom
- Corresponding author
- Gelfi, Cecilia
- ORCID
- Venue
- Journal of Proteome Research
- Publisher
- American Chemical Society (ACS)
- Published
- 2014-09-24
- Volume
- 13
- Issue
- 11
- Pages
- 5022-5030
- ISSN
- 1535-3893 (ISSN-L)
- 1535-3907
- OpenAlex
- W1973226334
- Cited by
- 40
- References
- 34
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2022: 5 · 2021: 2 · 2020: 2 · 2018: 5 · 2017: 6 · 2016: 8 · 2015: 5 · 2014: 1
- FWCI
- 2.73
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Proteome Research (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Funders
- European Commission (241665)
- Fondazione Telethon (GGP08017D, GGP110827)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Keywords
- Ullrich congenital muscular dystrophy, Bethlem myopathy, muscle proteome, endoplasmic reticulum stress, unfolded protein response, hexosamine biosynthetic pathway, autophagy dysfunction, lipotoxicity, amino acid metabolism, fatty acid metabolism, mechanotransduction, protein quality control, muscle degeneration
- MeSH terms
- Biopsy, Contracture, Fatty Acids, Hexosamines, Humans, Male, Muscular Dystrophies, Sclerosis, Immunoblotting, Reproducibility of Results, Case-Control Studies, Muscle, Skeletal, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Collagen Type VI, Proteomics, Unfolded Protein Response, Two-Dimensional Difference Gel Electrophoresis, Endoplasmic Reticulum Stress
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