Zinc deficiency contributes to blunted myogenesis in chronic kidney disease.

Frailty in patients with chronic kidney disease (CKD) greatly exacerbates disease comorbidities and increases probability of death. Prior research underscores molecular alterations in skeletal muscle physiology that may underly frailty and poor intervention response in this patient population. CKD can negatively affect satellite cell abundance and function, reducing skeletal muscle injury resilience and adaptive capacity. Pathogenic drivers of compromised satellite cell abundance and activity in patients with CKD remain largely unknown. To address this gap in knowledge, we isolated primary myogenic progenitor cells (MPCs) from patients with CKD and control participants. We also sought to define cell-extrinsic and cell-intrinsic processes that may underlie myogenic deficits. We performed RNA sequencing on MPCs from control participants cultured in control serum, MPCs from control participants cultured in CKD serum, and MPCs from participants with CKD cultured in control serum. We identified zinc mishandling as a shared pathway between control cells treated with CKD serum and CKD cells treated with control serum. Consistent with these observations, we found zinc deficiency and attenuated myogenesis in MPCs from patients with CKD. Finally, we showed that zinc supplementation partially restores the myogenic capacity of MPCs from patients with CKD. Together, these data highlight the importance of zinc metabolism in myogenesis and identify a novel mechanism whereby CKD pathogenesis impedes MPC differentiation.NEW & NOTEWORTHY Satellite cell abundance and function are negatively affected by chronic kidney disease (CKD). Using primary myogenic progenitor cells (MPCs) cultured from patients with late-stage CKD and matched controls, we expose cells to CKD or control serum and identify metallothionein-induced zinc deficiency as both a cell-autonomous and nonautonomous consequence of CKD on MPCs. We find zinc deficiency likely attenuates myogenesis through an AKT-FOXO1 signaling cascade, which can be partially rescued by supplementation of exogenous zinc.