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Although the mechanisms of myofibre loss in CKD has been widely studied, the contribution of muscle precursor cell (MPC) senescence remains poorly understood. Senescent MPCs no longer proliferate and can produce proinflammatory factors or cytokines. In this study, we tested the hypothesis that the senescence associated secretory phenotype (SASP) of MPCs contributes to CKD\u2010induced muscle atrophy and weakness.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>CKD was induced in mice by 5\/6th nephrectomy. Kidney function, muscle size, and function were measured, and markers of atrophy, inflammation, and senescence were evaluated using immunohistochemistry, immunoblots, or qPCR. To study the impact of senescence, a senolytics cocktail of dasatinib\u00a0+\u00a0quercetin (D&amp;Q) was given orally to mice for 8\u00a0weeks. To investigate CKD\u2010induced senescence at the cellular level, primary MPCs were incubated with serum from CKD or control subjects. The roles of specific proteins in MPC senescence were studied using adenoviral transduction, siRNA, and plasmid transfection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In the hindlimb muscles of CKD mice, (i) the senescence biomarker SA\u2010\u03b2\u2010gal was sharply increased (~30\u2010fold); (ii) the DNA damage response marker \u03b3\u2010H2AX was increased 1.9\u2010fold; and (iii) the senescence pathway markers p21 and p16<jats:sup>INK4a<\/jats:sup> were increased 1.99\u2010fold and 2.82\u2010fold, respectively (all values, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), whereas p53 was unchanged. \u03b3\u2010H2AX, p21, and p16<jats:sup>INK4A<\/jats:sup> were negatively correlated at P\u00a0&lt;\u00a00.05 with gastrocnemius weight, suggesting a causal relationship with muscle atrophy. Administration of the senolytics cocktail to CKD mice for 8\u00a0weeks eliminated the disease\u2010related elevation of p21, p16<jats:sup>INK4a<\/jats:sup>, and \u03b3\u2010H2AX, abolished positive SA\u2010\u03b2\u2010gal, and depressed the high levels of the SASP cytokines, TNF\u2010\u03b1, IL\u20106, IL\u20101\u03b2, and IFN (all values, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Skeletal muscle weight, myofibre cross\u2010sectional area, and grip function were improved in CKD mice receiving D&amp;Q. Markers of protein degradation, inflammation, and MPCs dysfunction were also attenuated by D&amp;Q treatment compared with the vehicle treatment in 5\/6th nephrectomy mice (all values, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Uraemic serum induced senescence in cultured MPCs. Overexpression of FoxO1a in MPCs increased the number of p21<jats:sup>+<\/jats:sup> senescent cells, and p21 siRNA prevented uraemic serum\u2010induced senescence (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Senescent MPCs are likely to contribute to the development of muscle wasting during CKD by producing inflammatory cytokines. Limiting senescence with senolytics ameliorated muscle wasting and improved muscle strength in vivo and restored cultured MPC functions. These results suggest potential new therapeutic targets to improve muscle health and function in CKD.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13112","type":"journal-article","created":{"date-parts":[[2022,11,10]],"date-time":"2022-11-10T03:19:55Z","timestamp":1668050395000},"page":"126-141","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["The impact of senescence on muscle wasting in chronic kidney disease"],"prefix":"10.1002","volume":"14","author":[{"given":"Ying","family":"Huang","sequence":"first","affiliation":[{"name":"Renal Division, Department of Medicine Emory University  Atlanta Georgia USA"},{"name":"Department of Nephrology The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Wang","sequence":"additional","affiliation":[{"name":"Renal Division, Department of Medicine Emory University  Atlanta Georgia USA"},{"name":"Institute of Nephrology, Zhong Da Hospital Southeast University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faten","family":"Hassounah","sequence":"additional","affiliation":[{"name":"Renal Division, Department of Medicine Emory University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. Russ","family":"Price","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Brody School of Medicine East Carolina University  Greenville North Carolina USA"},{"name":"Department of Internal Medicine, Brody School of Medicine East Carolina University  Greenville North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet","family":"Klein","sequence":"additional","affiliation":[{"name":"Renal Division, Department of Medicine Emory University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamer M.A.","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Institute of Molecular Cardiology University of Louisville  Louisville Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhua","family":"Wang","sequence":"additional","affiliation":[{"name":"Renal Division, Department of Medicine Emory University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanie","family":"Park","sequence":"additional","affiliation":[{"name":"Renal Division, Department of Medicine Emory University  Atlanta Georgia USA"},{"name":"Nephrology Section Atlanta VA Medical Center  Decatur Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Cai","sequence":"additional","affiliation":[{"name":"Renal Division, Department of Medicine Emory University  Atlanta Georgia USA"},{"name":"Nephrology Section Atlanta VA Medical Center  Decatur Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuemei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Renal Division, Department of Medicine Emory University  Atlanta Georgia USA"},{"name":"Department of Pharmacology Fudan University School of Pharmacy  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1023-8499","authenticated-orcid":false,"given":"Xiaonan H.","family":"Wang","sequence":"additional","affiliation":[{"name":"Renal Division, Department of Medicine Emory University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,11,9]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)32977-0"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2014.112"},{"key":"e_1_2_7_4_1","first-page":"138","article-title":"Pathophysiological mechanisms leading to muscle loss in chronic kidney disease. 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