Figure 8.

Mechanisms responsible for MPC senescence in CKD. CKD induces DNA damage in MPCs and activates the FOXO1 transcription factor. DNA damage increases p16^INK4a whereas the activation of FOXO1 transcription factor increases p21. Both p16^INK4a and p21 are cyclin‐dependent kinase (CDKs) inhibitors, which prevent cell cycle progression and lead to cell senescence. MPC senescence prevents muscle progenitor proliferation and induces the SASP in MPCs which leads to their production of inflammatory mediators and subsequent muscle wasting. Administration of dasatinib plus quercetin (D&Q) reduces CKD‐induced muscle atrophy by downregulation of FoxO1 and P16^INK4a as well as inducing apoptosis of senescent cells. This reduction of senescent cells limits inflammation and attenuates muscle wasting and dysfunction.