Tetraspanin CD82 is necessary for muscle stem cell activation and supports dystrophic muscle function
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RESEARCH
Open Access
Tetraspanin CD82 is necessary for muscle stem cell activation and supports dystrophic muscle function Arielle Hall1†, Tatiana Fontelonga1†, Alec Wright1, Katlynn Bugda Gwilt2, Jeffrey Widrick1, Alessandra Pasut3, Francesco Villa4, Cynthia K. Miranti5, Devin Gibbs6, Evan Jiang7, Hui Meng8, Michael W. Lawlor8 and Emanuela Gussoni1,9*
Abstract Background: Tetraspanins are a family of proteins known to assemble protein complexes at the cell membrane. They are thought to play diverse cellular functions in tissues by modifying protein-binding partners, thus bringing complexity and diversity in their regulatory networks. Previously, we identified the tetraspanin KAI/CD82 as a prospective marker for human muscle stem cells. CD82 expression appeared decreased in human Duchenne muscular dystrophy (DMD) muscle, suggesting a functional link to muscular dystrophy, yet whether this decrease is a consequence of dystrophic pathology or a compensatory mechanism in an attempt to rescue muscle from degeneration is currently unknown. Methods: We studied the consequences of loss of CD82 expression in normal and dystrophic skeletal muscle and examined the dysregulation of downstream functions in mice aged up to 1 year. Results: Expression of CD82 is important to sustain satellite cell activation, as in its absence there is decreased cell proliferation and less efficient repair of injured muscle. Loss of CD82 in dystrophic muscle leads to a worsened phenotype compared to control dystrophic mice, with decreased pulmonary function, myofiber size, and muscle strength. Mechanistically, decreased myofiber size in CD82−/− dystrophic mice is not due to altered PTEN/AKT signaling, although increased phosphorylation of mTOR at Ser2448 was observed. Conclusion: Basal CD82 expression is important to dystrophic muscle, as its loss leads to significantly weakened myofibers and impaired muscle function, accompanied by decreased satellite cell activity that is unable to protect and repair myofiber damage. Keywords: Tetraspanin, Stem cells, Muscular dystrophy, Regeneration, mTOR, AKT
* Correspondence: [email protected] † Arielle Hall and Tatiana Fontelonga contributed equally to this work. 1 Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA 02115, USA 9 The Stem Cell Program at Boston Children’s Hospital, Boston, MA 02115, USA Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article
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