Stonadge, Amy, Genzor, Aitana V, Russell, Alex et al. (6 more authors) (2023) Myofibrillar myopathy hallmarks associated with ZAK deficiency. Human Molecular Genetics. pp. 2751-2770. ISSN 0964-6906
Abstract
The ZAK gene encodes two functionally distinct kinases, ZAKα and ZAKβ. Homozygous loss of function mutations affecting both isoforms causes a congenital muscle disease. ZAKβ is the only isoform expressed in skeletal muscle and is activated by muscle contraction and cellular compression. The ZAKβ substrates in skeletal muscle or the mechanism whereby ZAKβ senses mechanical stress remains to be determined. To gain insights into the pathogenic mechanism, we exploited ZAK-deficient cell lines, zebrafish, mice and a human biopsy. ZAK-deficient mice and zebrafish show a mild phenotype. In mice, comparative histopathology data from regeneration, overloading, ageing and sex conditions indicate that while age and activity are drivers of the pathology, ZAKβ appears to have a marginal role in myoblast fusion in vitro or muscle regeneration in vivo. The presence of SYNPO2, BAG3 and Filamin C (FLNC) in a phosphoproteomics assay and extended analyses suggested a role for ZAKβ in the turnover of FLNC. Immunofluorescence analysis of muscle sections from mice and a human biopsy showed evidence of FLNC and BAG3 accumulations as well as other myofibrillar myopathy markers. Moreover, endogenous overloading of skeletal muscle exacerbated the presence of fibres with FLNC accumulations in mice, indicating that ZAKβ signalling is necessary for an adaptive turnover of FLNC that allows for the normal physiological response to sustained mechanical stress. We suggest that accumulation of mislocalized FLNC and BAG3 in highly immunoreactive fibres contributes to the pathogenic mechanism of ZAK deficiency.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The Author(s) 2023. |
Keywords: | Animals,Humans,Mice,Adaptor Proteins, Signal Transducing/genetics,Apoptosis Regulatory Proteins/genetics,Filamins/genetics,Muscle, Skeletal/metabolism,Mutation,Myopathies, Structural, Congenital/metabolism,Protein Isoforms/genetics,Zebrafish/genetics,Zebrafish Proteins/genetics |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Biology (York) |
Depositing User: | Pure (York) |
Date Deposited: | 18 Jan 2024 09:10 |
Last Modified: | 26 Oct 2024 00:08 |
Published Version: | https://doi.org/10.1093/hmg/ddad113 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1093/hmg/ddad113 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:207962 |
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Description: Myofibrillar myopathy hallmarks associated with ZAK deficiency
Licence: CC-BY 2.5