Yuki Saito1† and Takako S. Chikenji 1,2 * †1

Department of Anatomy, Sapporo Medical University School of Medicine, Sapporo, Japan, 2 Department of Health Sciences, School of Medicine, Hokkaido University, Sapporo, Japan

Skeletal muscle undergoes vigorous tissue remodeling after injury. However, aging, chronic inflammatory diseases, sarcopenia, and neuromuscular disorders cause muscle loss and degeneration, resulting in muscular dysfunction. Cellular senescence, a state of irreversible cell cycle arrest, acts during normal embryonic development and remodeling after tissue damage; when these processes are complete, the senescent cells are eliminated. However, the accumulation of senescent cells is a hallmark of aging tissues or pathological contexts and may lead to progressive tissue degeneration. The mechanisms responsible for the effects of senescent cells have not been fully elucidated. Here, we review current knowledge about the beneficial and detrimental effects of senescent cells in tissue repair, regeneration, aging, and age-related disease, especially in skeletal muscle. We also discuss how senescence of muscle stem cells and muscle-resident fibro-adipogenic progenitors affects muscle pathologies or regeneration, and consider the possibility that immunosenescence leads to muscle pathogenesis. Finally, we explore senotherapy, the therapeutic targeting of senescence to treat agerelated disease, from the standpoint of improving muscle regeneration.

Keywords: senescence, skeletal muscle, chronic inflammation, aging, muscle regeneration, muscle stem cells, FAPs, fibrosis

Edited by:

Barbara St. Pierre Schneider, University of Nevada, Las Vegas, United States

Reviewed by: Keitaro Yamanouchi, The University of Tokyo, Japan Antoneta Granic, Newcastle University, United Kingdom

*Correspondence: Takako S. Chikenji 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。†

ORCID: Yuki Saito orcid.org/0000-0002-7949-1628 Takako S. Chikenji orcid.org/0000-0003-2832-3656

Specialty section: This article was submitted to Inflammation Pharmacology, a section of the journal Frontiers in Pharmacology

Received: 11 July 2021

Accepted: 23 August 2021

Published: 06 September 2021

Citation: Saito Y and Chikenji TS (2021) Diverse Roles of Cellular Senescence in Skeletal Muscle Inflammation, Regeneration, and Therapeutics. Front. Pharmacol. 12:739510.

doi: 10.3389/fphar.2021.739510

Arisa Kita1,2 , Sena Yamamoto3 , Yuki Saito1 * and Takako S. Chikenji 3 *

1 Department of Anatomy, Sapporo Medical University School of Medicine, Sapporo, Japan, 2 Department of Plastic and Reconstructive Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan,

3 Graduate School of Health Sciences, Hokkaido University, Sapporo, Japan

Cellular senescence is a biological mechanism that prevents abnormal cell proliferation during tissue repair, and it is often accompanied by the secretion of various factors, such as cytokines and chemokines, known as the senescenceassociated secretory phenotype (SASP). SASP-mediated cell-to-cell communication promotes tissue repair, regeneration, and development. However, senescent cells can accumulate abnormally at injury sites, leading to excessive inflammation, tissue dysfunction, and intractable wounds. The effects of cellular senescence on skin wound healing can be both beneficial and detrimental, depending on the condition. Here, we reviewed the functional differences in cellular senescence that emerge during wound healing, chronic inflammation, and skin aging. We also review the latest mechanisms of wound healing in the epidermis, dermis, and subcutaneous fat, with a focus on cellular senescence, chronic inflammation, and tissue regeneration. Finally, we discuss the potential clinical applications of promoting and inhibiting cellular senescence to maximize benefits and minimize detrimental effects.

KEYWORDS

cellular senescence, senescence-associated secretory phenotypes (SASP), woundhealing, aged-skin, diabetic skin

EDITED BY

Chengliang Deng, Affiliated Hospital of Zunyi Medical University, China

REVIEWED BY

Eleni Mavrogonatou, National Centre of Scientific Research Demokritos, Greece Mariaceleste Aragona, University of Copenhagen, Denmark

*CORRESPONDENCE Takako S. Chikenji, 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 Yuki Saito, 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。

RECEIVED 25 November 2023

ACCEPTED 05 February 2024

PUBLISHED 19 February 2024

CITATION

Kita A, Yamamoto S, Saito Y and Chikenji TS (2024), Cellular senescence and wound healing in aged and diabetic skin. Front. Physiol. 15:1344116.

doi: 10.3389/fphys.2024.1344116

COPYRIGHT

© 2024 Kita, Yamamoto, Saito and Chikenji. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these  terms.

Michael Gold MD FAAD¹ | Yoon-Soo Cindy Bae MD FAAD² | David J. Goldberg MD JD FAAD^3,4 | Sumayah Jamal MD PhD⁵ | Amy B. Lewis MD⁶ | Shari Marchbein MD FAAD⁷ | Adriana Ros DO⁸ | Uma Santhanam PhD⁹ | Lisa DiNatale^9,10 | Jaime Emmetsberger PhD^9,10

田潇雨 卢娜

中国药科大学，中国·江苏 南京 210000

摘 要

衰老(Senecence)是细胞功能逐渐退化的一种状态，在这种状态下细胞几乎丧失复制能力，并且细胞周期抑制基因p16INK4a 的表达升高。细胞衰老贯穿生物个体的整个生命过程，在各种生理以及病理过程中发挥重要的作用。一方面，衰老的细胞能够促进胚胎发育，伤口愈合和宿主免疫反应以及抑制肿瘤发生发展等。另一方面，随着年龄增长而在体内积累的衰老细胞也会对机体带来有害的影响。这些不能增殖的细胞产生衰老相关分泌表型(Senescence-Associated Secretory PhenotypeSASP)，促进衰老相关疾病(Aging-related Diseae)的发生发展，而清除衰老细胞能够减缓衰老相关疾病的症状。因此寻找能够特异性杀死衰老细胞的药物(Senolytics)成为了抗衰老领域的研究重点。

关键词
细胞衰老;衰老相关分泌表型;衰老相关疾病;抗衰老;Senolytics

Advances in Research on Senescence in Health and Diseases

Xiaoyu Tian Na Lu

China Pharmaceutical University, Nanjing, Jiangsu, 210000, China

AbstractSenescence is a state in which the cell's functional characteristics are gradually deteriorating, in which the cell is at a sustained lowevel ofreplication and is accompanied by an increase in the expression of the cell cycle inhibitor pl6lNK4a The production of senescent cells occurs throughout life and plays key roles in various physiological and pathological proceses. These noneproliferating celsoccupy key cellular niches and produce senescence-associated secretory phenotype (SASP) which contributes to aging-related diseasesprogress. Therefore, the search for Senolytics has become the focus ofresearch in the field of anti-aging.

Keywords
cellular senescence, SASP, aging-related disease, anti-senescence, senolytics