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

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

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. Abstract: 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.

Citation

Crossland, H., Smith, K., Idris, I., Phillips, B. E., Atherton, P. J., & Wilkinson, D. J. (2021). Phenylbutyrate, a branched-chain amino acid keto dehydrogenase activator, promotes branched-chain amino acid metabolism and induces muscle catabolism in C2C12 cells. Experimental Physiology, 106(3), 585-592. https://doi.org/10.1113/EP089223

• Journal Article Type: Article
• Acceptance Date: Dec 22, 2020
• Online Publication Date: Dec 28, 2020
• Publication Date: Mar 1, 2021
• Deposit Date: Jan 5, 2021
• Publicly Available Date: Dec 29, 2021
• Journal: Experimental Physiology
• Print ISSN: 0958-0670
• Electronic ISSN: 1469-445X
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 106
• Issue: 3
• Pages: 585-592
• DOI: https://doi.org/10.1113/EP089223
• Keywords: Physiology
• Public URL: https://nottingham-repository.worktribe.com/output/5184242
• Publisher URL: https://physoc.onlinelibrary.wiley.com/doi/full/10.1113/EP089223