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

Storey, Emily; Holt, Ian; Brown, Sharon; Synowsky, Silvia; Shirran, Sally; Fuller, Heidi

Abstract

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. [Abstract copyright: Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.]

Citation

Storey, E., Holt, I., Brown, S., Synowsky, S., Shirran, S., & Fuller, H. (2024). Proteomic characterization of human LMNA-related congenital muscular dystrophy muscle cells. Neuromuscular Disorders, 38, 26-41. https://doi.org/10.1016/j.nmd.2024.03.006

• Journal Article Type: Article
• Acceptance Date: Mar 11, 2024
• Online Publication Date: Mar 15, 2024
• Publication Date: 2024-05
• Deposit Date: Mar 12, 2024
• Publicly Available Date: Mar 19, 2024
• Journal: Neuromuscular Disorders
• Print ISSN: 0960-8966
• Electronic ISSN: 1873-2364
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 38
• Pages: 26-41
• DOI: https://doi.org/10.1016/j.nmd.2024.03.006
• Keywords: L-CMD; lamin A; LMNA; congenital muscular dystrophy; emerin; SUN2; proteome; proteomics
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0960896624000592