Research Paper Volume 14, Issue 19 pp 7650—7661
Senolytic elimination of senescent macrophages restores muscle stem cell function in severely dystrophic muscle
- 1 Shandong The First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- 2 Center for Regenerative Sports Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA
- 3 University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- 4 Department of Biochemistry, Molecular Biology and Biophysics, Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN 55455, USA
Received: June 2, 2022 Accepted: August 25, 2022 Published: September 8, 2022
https://doi.org/10.18632/aging.204275How to Cite
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.
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.