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Crossland H, Smith K, Idris I, et al. Phenylbutyrate, a branched-chain amino acid keto dehydrogenase activator, promotes branched-chain amino acid metabolism and induces muscle catabolism in C2C12 cells. Exp Physiol. 2021;106(3):585-592doi: 10.1113/EP089223.
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
Crossland, Hannah, et al. "Phenylbutyrate, a branched-chain amino acid keto dehydrogenase activator, promotes branched-chain amino acid metabolism and induces muscle catabolism in C2C12 cells." Experimental physiology vol. 106,3 (2021): 585-592. doi: https://doi.org/10.1113/EP089223
Crossland H, Smith K, Idris I, Phillips BE, Atherton PJ, Wilkinson DJ. Phenylbutyrate, a branched-chain amino acid keto dehydrogenase activator, promotes branched-chain amino acid metabolism and induces muscle catabolism in C2C12 cells. Exp Physiol. 2021 Mar;106(3):585-592. doi: 10.1113/EP089223. Epub 2021 Jan 20. PMID: 33369803.
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Exp Physiol. 2021 Mar;106(3):585-592. doi: 10.1113/EP089223. Epub 2021 Jan 20.

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

Experimental physiology

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

Affiliations

  1. MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, National Institute for Health Research (NIHR) Biomedical Research Centre (BRC), Clinical, Metabolic and Molecular Physiology, University of Nottingham, Royal Derby Hospital, Derby, UK.

PMID: 33369803 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.

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.

© 2020 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

Keywords: branched-chain amino acids; mTOR; muscle protein synthesis; phenylbutyrate; skeletal muscle

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