Proteomic characterization of human LMNA-related congenital muscular dystrophy muscle cells.

Autor: Storey EC; Wolfson Centre for Inherited Neuromuscular Disease, RJAH Orthopaedic Hospital, Oswestry, SY10 7AG, UK; The School of Pharmacy and Bioengineering, Keele University, ST5 5BG, UK., Holt I; Wolfson Centre for Inherited Neuromuscular Disease, RJAH Orthopaedic Hospital, Oswestry, SY10 7AG, UK; The School of Pharmacy and Bioengineering, Keele University, ST5 5BG, UK., Brown S; Wolfson Centre for Inherited Neuromuscular Disease, RJAH Orthopaedic Hospital, Oswestry, SY10 7AG, UK; The School of Pharmacy and Bioengineering, Keele University, ST5 5BG, UK., Synowsky S; BSRC Mass Spectrometry and Proteomics Facility, University of St Andrews, KY16 9ST, UK., Shirran S; BSRC Mass Spectrometry and Proteomics Facility, University of St Andrews, KY16 9ST, UK., Fuller HR; Wolfson Centre for Inherited Neuromuscular Disease, RJAH Orthopaedic Hospital, Oswestry, SY10 7AG, UK; The School of Pharmacy and Bioengineering, Keele University, ST5 5BG, UK. Electronic address: h.r.fuller@keele.ac.uk.
Jazyk: angličtina
Zdroj: Neuromuscular disorders : NMD [Neuromuscul Disord] 2024 May; Vol. 38, pp. 26-41. Date of Electronic Publication: 2024 Mar 15.
DOI: 10.1016/j.nmd.2024.03.006
Abstrakt: LMNA-related congenital muscular dystrophy (L-CMD) is caused by mutations in the LMNA gene, encoding lamin A/C. To further understand the molecular mechanisms of L-CMD, proteomic profiling using DIA mass spectrometry was conducted on immortalized myoblasts and myotubes from controls and L-CMD donors each harbouring a different LMNA mutation (R249W, del.32 K and L380S). Compared to controls, 124 and 228 differentially abundant proteins were detected in L-CMD myoblasts and myotubes, respectively, and were associated with enriched canonical pathways including synaptogenesis and necroptosis in myoblasts, and Huntington's disease and insulin secretion in myotubes. Abnormal nuclear morphology and reduced lamin A/C and emerin abundance was evident in all L-CMD cell lines compared to controls, while nucleoplasmic aggregation of lamin A/C was restricted to del.32 K cells, and mislocalization of emerin was restricted to R249W cells. Abnormal nuclear morphology indicates loss of nuclear lamina integrity as a common feature of L-CMD, likely rendering muscle cells vulnerable to mechanically induced stress, while differences between L-CMD cell lines in emerin and lamin A localization suggests that some molecular alterations in L-CMD are mutation specific. Nonetheless, identifying common proteomic alterations and molecular pathways across all three L-CMD lines has highlighted potential targets for the development of non-mutation specific therapies.
Competing Interests: Declaration of competing interest The authors hereby confirm that they have nothing to declare in respect of the following manuscript:
(Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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