Kidney Week

Abstract: TH-PO435

An Epigenetic Mechanism Controls Muscle Protein Synthesis in Mice with CKD

Session Information

• Nutrition, Inflammation, Metabolism: Basic Mechanisms
  November 02, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Nutrition, Inflammation, and Metabolism

• 1401 Nutrition, Inflammation, Metabolism

Authors

• Zhang, Liping, Nephrology, Baylor College of Medicine, Houston, Texas, United States

Liping Zhang,

• Mitch, William E., Baylor College of Medicine, Houston, Texas, United States

William E. Mitch,

Background

For patients with chronic kidney disease (CKD), loss of muscle mass is frequent leading to morbidity. Unfortunately, there are no approved, regularly effective treatments that overcome muscle wasting in part because mechanisms causing muscle protein losses are still being uncovered. Previously, we showed that CKD induces loss of muscle via increased protein degradation with decreased protein synthesis. The former is due to activation of caspase-3 and the ubiquitin-proteasome system (UPS) but mechanisms impairing muscle protein synthesis are unknown. Now, we show that CKD stimulates a chromatin modifying protein, NO66, in muscle resulting in reduced protein synthesis.

Methods

Mice with whole body deletion of NO66 (NO66^-/-) were created by crossing transgenic, Sox2-cre mice with NO66^flox/flox mice. Mice with muscle-specific NO66 knockout (NO66^mko) were created by crossing tamoxifen-inducible, Pax7-cre mice with NO66^flox/flox mice. CKD (subtotal nephrectomy) was created in mice and those with BUN >80 mg/dL were studied

Results

Our hypothesis is that expression of NO66 in muscles suppresses protein synthesis. During testing of this hypothesis, we found that NO66^-/- mice exhibited a 20-30% increase in muscle mass vs. responses in NO66^flox/flox control mice. Secondly, in NO66^-/- mice the muscle wasting from CKD was blocked. To test the role of NO66 in muscle, we studied mice with muscle-specific NO66 KO (NO66^mko) and found there was an increase in muscle mass. To determine the mechanism underlying NO66-induced regulation of muscle mass in mice with CKD, we performed mass spectrometry assays and found that NO66 forms a repressive complex with two histone-modifying proteins, retinoblastoma binding protein 4 (RBBP4) and histone deacetylase 2 (HDAC2). This complex represses expression of muscle genes and the transcription of ribosomal DNA via a demethylase mechanism. Lastly, we performed a RNA-seq analysis using soleus muscles and identified that absence of NO66 stimulates a ribosomal biogenesis signaling pathway

Conclusion

We have uncovered a new CKD-initiated pathway that proceeds via a novel epigenetic mechanism that regulates muscle protein synthesis

Funding

• NIDDK Support –