Senolytic elimination of senescent macrophages restores muscle stem cell function in severely dystrophic muscle

Lei Liu, Xianlin Yue, Zewei Sun, William S. Hambright, Qi Feng, Yan Cui, Johnny Huard, Paul D. Robbins, Zhihui Wang, Xiaodong Mu

Research output: Contribution to journalArticlepeer-review

Abstract

The aging of the immune system, or immunosenescence, was recently verified to have a causal role in driving the aging of solid organs, while the senolytic elimination of senescent immune cells was found to effectively delay systemic aging. Our recent study also showed that immune cells in severely dystrophic muscles develop senescence-like phenotypes, including the increased expression of senescence-associated secretory phenotype (SASP) factors and senescence markers. Here we further investigated whether the specific clearance of senescent immune cells in dystrophic muscle may effectively improve the function of muscle stem cells and the phenotypes of dystrophic muscle. We observed increased percentage of senescent cells in macrophages from mdx/utro(−/−) mice (a murine model for muscular dystrophy disease, dystrophin−/−; utrophin−/−), while the treatment of mdx/utro(−/−) macrophages with senolytic drug fisetin resulted in reduced number of senescent cells. We administrated fisetin to mdx/utro(−/−) mice for 4 weeks, and observed obviously reduced number of senescent immune cells, restored number of muscle cells, and improve muscle phenotypes. In conclusion, our results reveal that senescent immune cells, such as macrophages, are greatly involved in the development of muscle dystrophy by impacting the function of muscle stem cells, and the senolytic ablation of these senescent cells with fisetin can be an effective therapeutic strategy for improving function of muscle stem cells and phenotypes of dystrophic muscles.

Original languageEnglish (US)
Pages (from-to)7650-7661
Number of pages12
JournalAging
Volume14
Issue number19
DOIs
StatePublished - 2022

Bibliographical note

Funding Information:
This study was supported by research funding from Shandong First Medical University and Shandong Academy of Medical Science to XM and ZW. This work was also supported by grant P01 AG062412 from the National Institutes of Health to PDR. We greatly appreciate the supports from the University of Texas Health Science Center at Houston.

Publisher Copyright:
© 2022 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Keywords

  • Cellular senescence
  • Immunosenescence
  • Muscular dystrophy
  • Senolytics
  • Stem cells

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Fingerprint

Dive into the research topics of 'Senolytic elimination of senescent macrophages restores muscle stem cell function in severely dystrophic muscle'. Together they form a unique fingerprint.

Cite this