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RCT disrupted the biomechanical equilibrium of the shoulder and decreased the mechanical stimuli transmitted to the rotator cuff. Whether mechanical stimuli participate in mediating muscular fatty infiltration after RCT remains unknown. The current study aimed to explore how mechanical environment changes caused by RCT affect muscular fatty infiltration and to identify the potential therapeutic modality.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Human and murine FAPs were isolated from RCT and control (CTRL) groups to compare adipogenesis properties. Single\u2010cell RNA sequencing and bulk RNA sequencing were performed to investigate the mechanisms of excessive adipogenesis of FAPs after RCT. The effects and mechanisms of PIEZO1 on adipogenesis of FAPs were investigated by small\u2010molecule treatment and FAP\u2010specific PIEZO1 knockout mice. The antiadipogenic effects of low\u2010intensity pulsed ultrasound (LIPUS) were investigated in\u00a0vitro and in\u00a0vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that the adipogenic differentiation ability of FAPs was increased after RCT (1.9\u2010fold vs. CTRL, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Single\u2010cell RNA\u2010sequencing data analyses and confirmation assays revealed suppressed expression of PIEZO1, which was proved by real\u2010time qPCR and Western blot (2.9\u2010fold vs. CTRL, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01, and 3.4\u2010fold vs. CTRL, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01). There was increased PPARG expression and adipogenesis ability of FAPs after PIEZO1 ablation (1.7\u2010fold vs. CTRL, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01, and 2.3\u2010fold vs. CTRL, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01). The PIEZO1\u2010mediated antiadipogenic role by ERK\/KLF4 signalling was confirmed by small\u2010molecule treatment and <jats:italic>PIEZO1 KO<\/jats:italic> mice evaluation. LIPUS could reactivate PIEZO1 and mitigate the adipogenesis of FAPs in\u00a0vitro, ameliorate the muscular fatty degeneration after RCT (3.0\u2010fold vs. CTRL, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) and facilitate the improvement of shoulder functions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings indicate that the downregulation of PIEZO1 expression contributes to the enhanced adipogenesis capacity of FAPs after RCT by inhibiting ERK\/KLF4 signalling. LIPUS could mitigate the excessive adipogenesis of FAPs by upregulating expression of PIEZO1, alleviate muscular fatty infiltration and improve shoulder function after RCT.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.70004","type":"journal-article","created":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T08:38:38Z","timestamp":1753778318000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Unravelling the Role of PIEZO1 in Adipogenesis of Fibrogenic\/Adipogenic Progenitors for Muscle Fat Infiltration After Rotator Cuff Tear"],"prefix":"10.1002","volume":"16","author":[{"given":"Xingzuan","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery and Spine Center Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"Department of Sports Medicine and Rehabilitation Peking University Third Hospital, Institute of Sports Medicine of Peking University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingfa","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Sports Medicine and Rehabilitation Peking University Third Hospital, Institute of Sports Medicine of Peking University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amila","family":"Kuati","sequence":"additional","affiliation":[{"name":"Department of Sports Medicine and Rehabilitation Peking University Third Hospital, Institute of Sports Medicine of Peking University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhanghua","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Wuhan Third Hospital, Tongren Hospital of Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Sports Medicine and Rehabilitation Peking University Third Hospital, Institute of Sports Medicine of Peking University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shujing","family":"Feng","sequence":"additional","affiliation":[{"name":"School of Exercise and Health Shanghai University of Sport  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minhui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, Fujian Key Laboratory of Medical Bioinformatics, School of Medical Technology and Engineering Fujian Medical University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyuan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery and Spine Center Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoqing","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Sports Medicine and Rehabilitation Peking University Third Hospital, Institute of Sports Medicine of Peking University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery and Spine Center Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiexiang","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery and Spine Center Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai 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