The impact of senescence on muscle wasting in chronic kidney disease

• DOI: 10.1002/jcsm.13112
• Publication Date: 2022-11-10T03:19:55Z
• Authors: Ying Huang; Bin Wang; Faten Hassounah; S. Russ Price; Janet Klein; Tamer M.A. Mohamed; Yanhua Wang; Jeanie Park; Hui Cai; Xuemei Zhang; Xiaonan H. Wang
• Keywords: Senescence; Muscle Atrophy; Proinflammatory cytokine

Abstract Background Muscle wasting is a common complication of chronic kidney disease (CKD) that associated with higher mortality. Although the mechanisms myofibre loss in CKD has been widely studied, contribution 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 hypothesis secretory phenotype (SASP) contributes to CKD‐induced atrophy weakness. Methods was induced mice by 5/6th nephrectomy. Kidney function, size, function were measured, markers atrophy, inflammation, evaluated using immunohistochemistry, immunoblots, qPCR. To study impact senescence, senolytics cocktail dasatinib + quercetin (D&Q) given orally for 8 weeks. investigate at cellular level, primary incubated serum from control subjects. The roles specific proteins MPC studied adenoviral transduction, siRNA, plasmid transfection. Results hindlimb muscles mice, (i) biomarker SA‐β‐gal sharply increased (~30‐fold); (ii) DNA damage response marker γ‐H2AX 1.9‐fold; (iii) pathway p21 p16 INK4a 1.99‐fold 2.82‐fold, respectively (all values, P < 0.05), whereas p53 unchanged. γ‐H2AX, p21, INK4A negatively correlated 0.05 gastrocnemius weight, suggesting causal relationship atrophy. Administration weeks eliminated disease‐related elevation , abolished positive SA‐β‐gal, depressed high levels SASP cytokines, TNF‐α, IL‐6, IL‐1β, IFN 0.05). Skeletal cross‐sectional area, grip improved receiving D&Q. Markers protein degradation, dysfunction also attenuated D&Q treatment compared vehicle nephrectomy Uraemic cultured MPCs. Overexpression FoxO1a number senescent cells, siRNA prevented uraemic serum‐induced ( Conclusions are likely contribute development during producing inflammatory Limiting ameliorated strength vivo restored functions. These results suggest potential new therapeutic targets improve health CKD.