Phenylbutyrate, a branched-chain amino acid keto dehydrogenase activator, promotes branched-chain amino acid metabolism and induces muscle catabolism in C2C12 cells.

Hannah Crossland,Philip J Atherton,Bethan E Phillips,Kenneth Smith,Daniel J Wilkinson,Iskandar Idris

doi:10.1113/ep089223

Abstract

New Findings What is the central question of this study? The compound sodium phenylbutyrate (PB) has been shown to promote branched‐chain amino acid (BCAA) catabolism, and as such has been proposed as a treatment for disorders with enhanced BCAA levels: does PB induce muscle protein catabolism by forcing BCAA degradation away from muscle protein synthesis and mechanistic target of rapamycin (mTOR) inhibition? What is the main finding and its importance? Accelerated BCAA catabolism using PB resulted in adverse effects related to mTOR signalling and muscle protein metabolism in skeletal muscle cells, which may limit its application in conditions where muscle wasting is a risk. The compound sodium phenylbutyrate (PB) has been used for reducing ammonia in patients with urea cycle disorders and proposed as a treatment for disorders with enhanced branched‐chain amino acid (BCAA) levels, due to its effects on promoting BCAA catabolism. In skeletal muscle cells, we hypothesised that PB would induce muscle protein catabolism due to forcing BCAA degradation away from muscle protein synthesis and downregulating mechanistic target of rapamycin (mTOR). PB reduced medium BCAA and branched‐chain keto acid (BCKA) concentrations, while total cell protein (−21%; P < 0.001 vs. control) and muscle protein synthesis (−25%; P < 0.001 vs. control; assessed by measurement of puromycin incorporation into polypeptides) were decreased with PB. The regulator of anabolic pathways mTOR and its downstream components were impaired with PB treatment. The present results indicate that accelerated BCAA catabolism using PB resulted in adverse effects related to mTOR signalling and muscle protein metabolism, which may limit its application in settings where muscle wasting is a risk.

Highlights

The compound sodium phenylbutyrate (PB) has been successfully used as an ammonia-lowering drug for patients with urea cycle disorders (UCDs), whereby nitrogen is disposed of in the urine in the form of phenylacetylglutamine (Brusilow, 1991)
For medium branched-chain amino acid (BCAA) and KIC, there were no differences in concentrations between 6 and 24 h in either control or PB-treated cells, but there was a relative increase in medium KIV (P = 0.02 vs. 6 h) and KMV (P = 0.026 vs. 6 h) between time points with PB treatment (Figure 1e, f)
Administration of PB has been used as an ammonia-lowering drug for patients with UCD (Brusilow, 1991), but depletion of circulating BCAA has been observed in these patients (Scaglia et al, 2004), and PB has directly been shown to activate the branched-chain keto acid (BCKA) dehydrogenase complex (Brunetti-Pierri et al, 2011)

Summary

Introduction

The compound sodium phenylbutyrate (PB) has been successfully used as an ammonia-lowering drug for patients with urea cycle disorders (UCDs), whereby nitrogen is disposed of in the urine in the form of phenylacetylglutamine (Brusilow, 1991). The exact mechanisms by which PB may exert beneficial effects across a wide range of disorders remain unclear, one observed effect of PB treatment is decreased levels of endoplasmic reticulum (ER) stress (Kolb et al, 2015). Another observed consequence of PB treatment relates to its effect on branchedchain amino acid (BCAA) metabolism, where studies have reported substantial decreases in circulating BCAA concentrations with PB administration in patients with UCD (Scaglia, Carter, O’Brien, & Lee, 2004).

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