Detyrosinated microtubule arrays drive myofibrillar malformations in mdx muscle fibers
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), a...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-08-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2023.1209542/full |
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| author | 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 Anna Grosberg Anna Grosberg Christopher W. Ward Christopher W. Ward |
| author_facet | 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 Anna Grosberg Anna Grosberg Christopher W. Ward Christopher W. Ward |
| author_sort | Anicca D. Harriot |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T13:22:34Z |
| format | Article |
| id | doaj.art-a51700562a7c4ab8a3cb96c40aeb52a0 |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-03-12T13:22:34Z |
| publishDate | 2023-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-a51700562a7c4ab8a3cb96c40aeb52a02023-08-25T16:54:41ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2023-08-011110.3389/fcell.2023.12095421209542Detyrosinated microtubule arrays drive myofibrillar malformations in mdx muscle fibersAnicca D. Harriot0Tessa Altair Morris1Camilo Vanegas2Jacob Kallenbach3Kaylie Pinto4Humberto C. Joca5Marie-Jo Moutin6Guoli Shi7Jeanine A. Ursitti8Anna Grosberg9Anna Grosberg10Anna Grosberg11Christopher W. Ward12Christopher W. Ward13Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, United StatesCenter for Complex Biological Systems, Edwards Lifesciences Foundation Cardiovascular Innovation and Research Center, and the NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA, United StatesDepartment of Orthopedics, University of Maryland School of Medicine, Baltimore, MD, United StatesDepartment of Orthopedics, University of Maryland School of Medicine, Baltimore, MD, United StatesDepartment of Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD, United StatesDepartment of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, United StatesINSERM U1216 Centre National de la Recherche Scientifique, Grenoble Institut Neurosciences, University Grenoble Alpes, Grenoble, FranceDepartment of Orthopedics, University of Maryland School of Medicine, Baltimore, MD, United StatesDepartment of Orthopedics, University of Maryland School of Medicine, Baltimore, MD, United StatesCenter for Complex Biological Systems, Edwards Lifesciences Foundation Cardiovascular Innovation and Research Center, and the NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA, United StatesDepartment of Biomedical Engineering, Sue and Bill Gross Stem Cell Research, University of California, Irvine, Irvine, CA, United StatesDepartment of Chemical and Biomolecular Engineering, Sue and Bill Gross Stem Cell Research, University of California, Irvine, Irvine, CA, United StatesDepartment of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, United StatesDepartment of Orthopedics, University of Maryland School of Medicine, Baltimore, MD, United StatesAltered 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.https://www.frontiersin.org/articles/10.3389/fcell.2023.1209542/fulldystrophyskeletal musclemyoarchitecturemicrotubule arraydetyrosination |
| spellingShingle | 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 Anna Grosberg Anna Grosberg Christopher W. Ward Christopher W. Ward Detyrosinated microtubule arrays drive myofibrillar malformations in mdx muscle fibers Frontiers in Cell and Developmental Biology dystrophy skeletal muscle myoarchitecture microtubule array detyrosination |
| title | Detyrosinated microtubule arrays drive myofibrillar malformations in mdx muscle fibers |
| title_full | Detyrosinated microtubule arrays drive myofibrillar malformations in mdx muscle fibers |
| title_fullStr | Detyrosinated microtubule arrays drive myofibrillar malformations in mdx muscle fibers |
| title_full_unstemmed | Detyrosinated microtubule arrays drive myofibrillar malformations in mdx muscle fibers |
| title_short | Detyrosinated microtubule arrays drive myofibrillar malformations in mdx muscle fibers |
| title_sort | detyrosinated microtubule arrays drive myofibrillar malformations in mdx muscle fibers |
| topic | dystrophy skeletal muscle myoarchitecture microtubule array detyrosination |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2023.1209542/full |
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