Branched Short-Chain Fatty Acid Isovaleric Acid Causes Colonic Smooth Muscle Relaxation via cAMP/PKA Pathway

  • Bryan A. Blakeney
  • Molly S. Crowe
  • Sunila Mahavadi
  • Karnam S. Murthy
  • John R. GriderEmail author
Original Article



Isovaleric acid (IVA) is a 5-carbon branched-chain fatty acid present in fermented foods and produced in the colon by bacterial fermentation of leucine. We previously reported that the shorter, straight-chain fatty acids acetate, propionate and butyrate differentially affect colonic motility; however, the effect of branched-chain fatty acids on gut smooth muscle and motility is unknown.


To determine the effect of IVA on contractility of colonic smooth muscle.


Murine colonic segments were placed in a longitudinal orientation in organ baths in Krebs buffer and fastened to force transducers. Segments were contracted with acetylcholine (ACh), and the effects of IVA on ACh-induced contraction were measured in the absence and presence of tetrodotoxin (TTx) or inhibitors of nitric oxide synthase [L-N-nitroarginine (L-NNA)] or adenylate cyclase (SQ22536). The effect of IVA on ACh-induced contraction was also measured in isolated muscle cells in the presence or absence of SQ22536 or protein kinase A (PKA) inhibitor (H-89). Direct activation of PKA was measured in isolated muscle cells.


In colonic segments, ACh-induced contraction was inhibited by IVA in a concentration-dependent fashion; the IVA response was not affected by TTx or L-NNA but inhibited by SQ22536. Similarly, in isolated colonic muscle cells, ACh-induced contraction was inhibited by IVA in a concentration-dependent fashion and the effect blocked by SQ22536 and H-89. IVA also increased PKA activity in isolated smooth muscle cells.


The branched-chain fatty acid IVA acts directly on colonic smooth muscle and causes muscle relaxation via the PKA pathway.


Colon Smooth muscle Isovaleric acid Branched-chain fatty acid Cyclic AMP Adenylyl cyclase Protein kinase A SQ22536 H-89 Tetrodotoxin Nitric oxide synthase L-N-nitroarginine 



This work was supported by grants DK34153 (JR Grider) and DK28300 and DK15564 (KS Murthy) from the National Institute of Diabetes and Kidney Diseases.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Bryan A. Blakeney
    • 1
  • Molly S. Crowe
    • 1
  • Sunila Mahavadi
    • 1
  • Karnam S. Murthy
    • 1
  • John R. Grider
    • 1
    Email author
  1. 1.Department of Physiology and Biophysics, VCU Program in Enteric Neuromuscular SciencesVirginia Commonwealth UniversityRichmondUSA

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