Murphy, Sandra and Zweyer, Margit and Henry, Michael and Meleady, Paula and Mundegar, Rustam R and Swandulla, Dieter and Ohlendieck, Kay
(2018)
Proteomic analysis of the sarcolemma-enriched fraction from dystrophic mdx-4cv skeletal muscle.
Journal of Proteomics, 191.
pp. 212-227.
ISSN 1874-3919
Abstract
The highly progressive neuromuscular disorder dystrophinopathy is triggered by primary abnormalities in the
Dmd gene, which causes cytoskeletal instability and loss of sarcolemmal integrity. Comparative organellar
proteomics was employed to identify sarcolemma-associated proteins with an altered concentration in dystrophic muscle tissue from the mdx-4cv mouse model of dystrophinopathy. A lectin agglutination method was
used to prepare a sarcolemma-enriched fraction and resulted in the identification of 190 significantly changed
protein species. Proteomics established differential expression patterns for key components of the muscle plasma
membrane, cytoskeletal network, extracellular matrix, metabolic pathways, cellular stress response, protein
synthesis, immune response and neuromuscular junction. The deficiency in dystrophin and drastic reduction in
dystrophin-associated proteins appears to trigger (i) enhanced membrane repair involving myoferlin, dysferlin
and annexins, (ii) increased protein synthesis and the compensatory up-regulation of cytoskeletal proteins, (iii)
the decrease in the scaffolding protein periaxin and myelin PO involved in myelination of motor neurons, (iv)
complex changes in bioenergetic pathways, (v) elevated levels of molecular chaperones to prevent proteotoxic
effects, (vi) increased collagen deposition causing reactive myofibrosis, (vii) disturbed ion homeostasis at the
sarcolemma and associated membrane systems, and (viii) a robust inflammatory response by the innate immune
system in response to chronic muscle damage.
Significance: Duchenne muscular dystrophy is a devastating muscle wasting disease and represents the most
frequently inherited neuromuscular disorder in humans. Genetic abnormalities in the Dmd gene cause a loss of
sarcolemmal integrity and highly progressive muscle fibre degeneration. Changes in the neuromuscular system
are associated with necrosis, fibrosis and inflammation. In order to evaluate secondary changes in the sarcolemma membrane system due to the lack of the membrane cytoskeletal protein dystrophin, comparative organellar proteomics was used to study the mdx-4cv mouse model of dystrophinopathy. Mass spectrometric analyses
identified a variety of altered components of the extracellular matrix-sarcolemma-cytoskeleton axis in dystrophic
muscles. This included proteins involved in membrane repair, cytoskeletal restoration, calcium homeostasis,
cellular signalling, stress response, neuromuscular transmission and reactive myofibrosis, as well as immune cell
infiltration. These pathobiochemical alterations agree with the idea of highly complex secondary changes in Xlinked muscular dystrophy and support the concept that micro-rupturing of the dystrophin-deficient plasma
membrane is at the core of muscle wasting pathology
Item Type: |
Article
|
Keywords: |
Biglycan;
Dysferlin;
Myelin PO;
Myoferlin;
Periaxin;
Synemin; |
Academic Unit: |
Faculty of Science and Engineering > Biology |
Item ID: |
13140 |
Identification Number: |
https://doi.org/10.1016/j.jprot.2018.01.015 |
Depositing User: |
Prof. Kay Ohlendieck
|
Date Deposited: |
22 Jul 2020 15:28 |
Journal or Publication Title: |
Journal of Proteomics |
Publisher: |
Elsevier |
Refereed: |
Yes |
Funders: |
Hume scholarship (Maynooth University), Muscular Dystrophy Ireland, Health Research Board (HRB), Science Foundation Ireland (SFI) |
URI: |
|
Use Licence: |
This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available
here |
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