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MyD88 is required for satellite cell-mediated myofiber regeneration in dystrophin-deficient mdx mice.
Hum Mol Genet. 2018 10 01; 27(19):3449-3463.HM

Abstract

Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, leads to severe muscle wasting and eventual death of the afflicted individuals, primarily due to respiratory failure. Deficit in myofiber regeneration, potentially due to an exhaustion of satellite cells, is one of the major pathological features of DMD. Myeloid differentiation primary response 88 (MyD88) is an adaptor protein that mediates activation of various inflammatory pathways in response to signaling from Toll-like receptors and interleukin-1 receptor. MyD88 also regulates cellular survival, proliferation and differentiation in a cell-autonomous manner. However, the role of MyD88 in satellite stem cell homeostasis and function in dystrophic muscle remains unknown. In this study, we demonstrate that tamoxifen-inducible deletion of MyD88 in satellite cells causes loss of skeletal muscle mass and strength in the mdx mouse model of DMD. Satellite cell-specific deletion of MyD88 inhibits myofiber regeneration and stimulates fibrogenesis in dystrophic muscle of mdx mice. Deletion of MyD88 also reduces the number of satellite cells and inhibits their fusion with injured myofibers in dystrophic muscle of mdx mice. Ablation of MyD88 in satellite cells increases the markers of M2 macrophages without having any significant effect on M1 macrophages and expression of inflammatory cytokines. Finally, we found that satellite cell-specific deletion of MyD88 leads to aberrant activation of Notch and Wnt signaling in skeletal muscle of mdx mice. Collectively, our results demonstrate that MyD88-mediated signaling in satellite cells is essential for the regeneration of injured myofibers in dystrophic muscle of mdx mice.

Authors+Show Affiliations

Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY 40202, USA.Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY 40202, USA.Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY 40202, USA.Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY 40202, USA.Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY 40202, USA.Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY 40202, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

30010933

Citation

Gallot, Yann S., et al. "MyD88 Is Required for Satellite Cell-mediated Myofiber Regeneration in Dystrophin-deficient Mdx Mice." Human Molecular Genetics, vol. 27, no. 19, 2018, pp. 3449-3463.
Gallot YS, Straughn AR, Bohnert KR, et al. MyD88 is required for satellite cell-mediated myofiber regeneration in dystrophin-deficient mdx mice. Hum Mol Genet. 2018;27(19):3449-3463.
Gallot, Y. S., Straughn, A. R., Bohnert, K. R., Xiong, G., Hindi, S. M., & Kumar, A. (2018). MyD88 is required for satellite cell-mediated myofiber regeneration in dystrophin-deficient mdx mice. Human Molecular Genetics, 27(19), 3449-3463. https://doi.org/10.1093/hmg/ddy258
Gallot YS, et al. MyD88 Is Required for Satellite Cell-mediated Myofiber Regeneration in Dystrophin-deficient Mdx Mice. Hum Mol Genet. 2018 10 1;27(19):3449-3463. PubMed PMID: 30010933.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - MyD88 is required for satellite cell-mediated myofiber regeneration in dystrophin-deficient mdx mice. AU - Gallot,Yann S, AU - Straughn,Alex R, AU - Bohnert,Kyle R, AU - Xiong,Guangyan, AU - Hindi,Sajedah M, AU - Kumar,Ashok, PY - 2018/03/26/received PY - 2018/07/09/accepted PY - 2018/7/17/pubmed PY - 2019/3/29/medline PY - 2018/7/17/entrez SP - 3449 EP - 3463 JF - Human molecular genetics JO - Hum Mol Genet VL - 27 IS - 19 N2 - Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, leads to severe muscle wasting and eventual death of the afflicted individuals, primarily due to respiratory failure. Deficit in myofiber regeneration, potentially due to an exhaustion of satellite cells, is one of the major pathological features of DMD. Myeloid differentiation primary response 88 (MyD88) is an adaptor protein that mediates activation of various inflammatory pathways in response to signaling from Toll-like receptors and interleukin-1 receptor. MyD88 also regulates cellular survival, proliferation and differentiation in a cell-autonomous manner. However, the role of MyD88 in satellite stem cell homeostasis and function in dystrophic muscle remains unknown. In this study, we demonstrate that tamoxifen-inducible deletion of MyD88 in satellite cells causes loss of skeletal muscle mass and strength in the mdx mouse model of DMD. Satellite cell-specific deletion of MyD88 inhibits myofiber regeneration and stimulates fibrogenesis in dystrophic muscle of mdx mice. Deletion of MyD88 also reduces the number of satellite cells and inhibits their fusion with injured myofibers in dystrophic muscle of mdx mice. Ablation of MyD88 in satellite cells increases the markers of M2 macrophages without having any significant effect on M1 macrophages and expression of inflammatory cytokines. Finally, we found that satellite cell-specific deletion of MyD88 leads to aberrant activation of Notch and Wnt signaling in skeletal muscle of mdx mice. Collectively, our results demonstrate that MyD88-mediated signaling in satellite cells is essential for the regeneration of injured myofibers in dystrophic muscle of mdx mice. SN - 1460-2083 UR - https://www.unboundmedicine.com/medline/citation/30010933/MyD88_is_required_for_satellite_cell_mediated_myofiber_regeneration_in_dystrophin_deficient_mdx_mice_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddy258 DB - PRIME DP - Unbound Medicine ER -