ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: PO2481

Does Senescence Induce Muscle Wasting in CKD?

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Wang, Bin, Southeast University, Nanjing, Jiangsu, China
  • Huang, Ying, Emory University School of Medicine, Atlanta, Georgia, United States
  • Klein, Janet D., Emory University School of Medicine, Atlanta, Georgia, United States
  • Cai, Hui, Emory University School of Medicine, Atlanta, Georgia, United States
  • Wang, Xiaonan H., Emory University School of Medicine, Atlanta, Georgia, United States
Background

Muscle wasting is a common complication of CKD and associated with higher mortality and morbidity. The mechanism of muscle wasting in uremia has been widely studied; however, uremic stress-induced senescence might be a missing connection between chronic kidney disease and muscle wasting. Senescent cells are capable of producing and secreting various growth and proinflammatory factors, cytokines, and chemokines, which is known as the S-ASP. We hypothesized that senescence and senescence associated secretary phenotype (S-ASP) play important roles in the CKD-induced muscle loss.

Methods

CKD mice were induced by 5/6 nephrectomy. Senescence was confirmed by using senescence associated beta gal (SA-βgal). The levels of S-ASP (interleukin 6 (IL-6), TNFα, TGFβ and IL-8) were measured by immunohistochemistry and ELISA. Senescence pathway markers p16, p21 and p53 were measured by Western blots. To limit senescence, dasatinib (5 mg/kg BW) + quercetin (50 mg/kg BW) (D&Q) were given by oral gavage 2 days per week for 8 weeks. Muscle function was measured with a grip force detector.

Results

CKD stress-induced premature senescence phenomena have been evidenced in the skeletal muscle of uremic mice by 1) the increases in senescence pathway indicators p21 and p16, but not p53 protein; 2) phosphorylated histone H2AX (γH2AX, DNA damage marker); 3) the level of the senescence biomarker SA-β gal; and 4) S-ASP components present in the uremic muscle, which include high levels of interleukin 6 (IL-6), TNFα, TGFβ and IL-8. The D&Q treatment eliminated CKD-induced elevation of p21, p16 and γH2AX, abolished positive SA-β gal, and depressed the high levels of S-ASP cytokines. The muscle cross-sectional area was increased by D&Q treatment compared with the vehicle treatment in 5/6 nephrectomy mice. Skeletal muscle function was also improved with D&Q treatment in uremic mice.

Conclusion

Senescence and S-ASP are important factors in development of muscle wasting during CKD progression. Limiting senescence with D&Q ameliorates muscle wasting and improves muscle function. These results provide new approaches for developing therapeutic strategies to improve muscle health in chronic kidney diseases.

Funding

  • Veterans Affairs Support