Journal
EXPERIMENTAL PHYSIOLOGY
Volume 106, Issue 3, Pages 585-592Publisher
WILEY
DOI: 10.1113/EP089223
Keywords
branched-chain amino acids; mTOR; muscle protein synthesis; phenylbutyrate; skeletal muscle
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Funding
- Medical Research Council, MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research award [MR/P021220/1]
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The compound sodium phenylbutyrate (PB) accelerates BCAA catabolism, leading to adverse effects on mTOR signaling and muscle protein metabolism, which may limit its application in settings 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.
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