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Detyrosinated microtubule arrays drive myofibrillar malformations in mdx muscle fibers

Authors :
Anicca D. Harriot
Tessa Altair Morris
Camilo Vanegas
Jacob Kallenbach
Kaylie Pinto
Humberto C. Joca
Marie-Jo Moutin
Guoli Shi
Jeanine A. Ursitti
Anna Grosberg
Christopher W. Ward
Source :
Frontiers in Cell and Developmental Biology, Vol 11 (2023)
Publication Year :
2023
Publisher :
Frontiers Media S.A., 2023.

Abstract

Altered myofibrillar structure is a consequence of dystrophic pathology that impairs skeletal muscle contractile function and increases susceptibility to contraction injury. In murine Duchenne muscular dystrophy (mdx), myofibrillar alterations are abundant in advanced pathology (>4 months), an age where we formerly established densified microtubule (MT) arrays enriched in detyrosinated (deTyr) tubulin as negative disease modifiers impacting cell mechanics and mechanotransduction. Given the essential role of deTyr-enriched MT arrays in myofibrillar growth, maintenance, and repair, we examined the increased abundance of these arrays as a potential mechanism for these myofibrillar alterations. Here we find an increase in deTyr-tubulin as an early event in dystrophic pathology (4 weeks) with no evidence myofibrillar alterations. At 16 weeks, we show deTyr-enriched MT arrays significantly densified and co-localized to areas of myofibrillar malformation. Profiling the enzyme complexes responsible for deTyr-tubulin, we identify vasohibin 2 (VASH2) and small vasohibin binding protein (SVBP) significantly elevated in the mdx muscle at 4 weeks. Using the genetic increase in VASH2/SVBP expression in 4 weeks wild-type mice we find densified deTyr-enriched MT arrays that co-segregate with myofibrillar malformations similar to those in the 16 weeks mdx. Given that no changes in sarcomere organization were identified in fibers expressing sfGFP as a control, we conclude that disease-dependent densification of deTyr-enriched MT arrays underscores the altered myofibrillar structure in dystrophic skeletal muscle fibers.

Details

Language :
English
ISSN :
2296634X
Volume :
11
Database :
Directory of Open Access Journals
Journal :
Frontiers in Cell and Developmental Biology
Publication Type :
Academic Journal
Accession number :
edsdoj.51700562a7c4ab8a3cb96c40aeb52a0
Document Type :
article
Full Text :
https://doi.org/10.3389/fcell.2023.1209542