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Abstract: FR-OR109

CKD Impairs Muscle Protein Synthesis via a Demethylase Mechanism That Regulates Ribosomal Biogenesis

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Zhang, Liping, Nephrology, Baylor College of Medicine, Houston, Texas, United States
  • Mitch, William E., Baylor College of Medicine, Houston, Texas, United States
Background

the report that patients with chronic kidney disease (CKD) require diets with 1.5 g protein/kg/d is based on the premise that a high protein diet will overcome a block in muscle protein synthesis. Such a diet, however, would cause metabolic acidosis, hyperphosphatemia, etc. To prevent these outcomes we are investigating mechanisms that can improve muscle protein synthesis even with dietary protein is restricted. We have identified a CKD-stimulated, chromatin-modifying, nucleolar protein, NO66 and show that it suppresses both ribosomal DNA transcription and muscle protein synthesis

Methods

we studied mice with CKD (subtotal nephrectomy) with BUN >80 mg/dL, similar to values in ESRD patients.

Results

NO66 demethylates histone proteins, H3K4ME3 and H3K36ME3, regulating growth. In muscles of both mice and patients with CKD, we found high levels of NO66 mRNA and protein. These increases were found to be stimulated by inflammation and mediated by changes in NF-κB: NO66 expression was suppressed by a NF-κB inhibitor. In support of this conclusion, we identified 3 NF-κB binding sites in the NO66 promoter. Does NO66 cause loss of muscle mass in mice with CKD? To address this possibility, we created global KO of NO66 in mice (NO66-/-) or satellite cell-specific NO66 KO (NO66-Pax7-cre) or muscle-specific NO66 KO (NO66-MCK-cre) mice. In response to CKD, NO66 KO mice developed an increase in muscle mass (28±8%) and protein synthesis (71±15%) vs. results in control mice. From a RNA-seq analysis of soleus muscles of NO66-/- and NO66flox/flox mice, we found that NO66 absence in muscle stimulates ribosomal biogenesis. Consistent with the RNA-seq results, both rRNA and the ribosomal translational capacity were increased in muscles lacking NO66 vs. results from control, NO66flox/flox mice. In addition, NO66 overexpression was found to suppress pre-rRNA expression in C2C12 muscle cells. Finally, a CHIP assay revealed that NO66 represses the transcription of ribosomal DNA via a demethylase mechanism

Conclusion

we have uncovered a new mechanism that regulates protein synthesis and ultimately, muscle mass

Funding

  • NIDDK Support