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Overexpression of Long-Chain Acyl-CoA Synthetase 5 Increases Fatty Acid Oxidation and Free Radical Formation While Attenuating Insulin Signaling in Primary Human Skeletal Myotubes

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  • Hyo-Bum Kwak

    (Department of Physiology, East Carolina University, Greenville, NC 27858, USA
    Department of Kinesiology, East Carolina University, Greenville, NC 27858, USA
    Department of Kinesiology, Inha University, Incheon 22212, Korea)

  • Tracey L. Woodlief

    (Department of Kinesiology, East Carolina University, Greenville, NC 27858, USA
    Department of Pharmacology and Toxicology, East Carolina University, Greenville, NC 27858, USA)

  • Thomas D. Green

    (Department of Physiology, East Carolina University, Greenville, NC 27858, USA
    Department of Internal Medicine, East Carolina University, Greenville, NC 27858, USA)

  • Julie H. Cox

    (Department of Kinesiology, East Carolina University, Greenville, NC 27858, USA)

  • Robert C. Hickner

    (Department of Nutrition, Food and Exercise Sciences, Florida State University, Tallahassee, FL 32306, USA)

  • P. Darrell Neufer

    (Department of Physiology, East Carolina University, Greenville, NC 27858, USA
    The East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27858, USA)

  • Ronald N. Cortright

    (Department of Physiology, East Carolina University, Greenville, NC 27858, USA
    Department of Kinesiology, East Carolina University, Greenville, NC 27858, USA
    The East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27858, USA)

Abstract

In rodent skeletal muscle, acyl-coenzyme A (CoA) synthetase 5 (ACSL-5) is suggested to localize to the mitochondria but its precise function in human skeletal muscle is unknown. The purpose of these studies was to define the role of ACSL-5 in mitochondrial fatty acid metabolism and the potential effects on insulin action in human skeletal muscle cells (HSKMC). Primary myoblasts isolated from vastus lateralis (obese women (body mass index (BMI) = 34.7 ± 3.1 kg/m 2 )) were transfected with ACSL-5 plasmid DNA or green fluorescent protein (GFP) vector (control), differentiated into myotubes, and harvested (7 days). HSKMC were assayed for complete and incomplete fatty acid oxidation ([1- 14 C] palmitate) or permeabilized to determine mitochondrial respiratory capacity (basal (non-ADP stimulated state 4), maximal uncoupled (carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone (FCCP)-linked) respiration, and free radical (superoxide) emitting potential). Protein levels of ACSL-5 were 2-fold higher in ACSL-5 overexpressed HSKMC. Both complete and incomplete fatty acid oxidation increased by 2-fold ( p < 0.05). In permeabilized HSKMC, ACSL-5 overexpression significantly increased basal and maximal uncoupled respiration ( p < 0.05). Unexpectedly, however, elevated ACSL-5 expression increased mitochondrial superoxide production (+30%), which was associated with a significant reduction ( p < 0.05) in insulin-stimulated p-Akt and p-AS160 protein levels. We concluded that ACSL-5 in human skeletal muscle functions to increase mitochondrial fatty acid oxidation, but contrary to conventional wisdom, is associated with increased free radical production and reduced insulin signaling.

Suggested Citation

  • Hyo-Bum Kwak & Tracey L. Woodlief & Thomas D. Green & Julie H. Cox & Robert C. Hickner & P. Darrell Neufer & Ronald N. Cortright, 2019. "Overexpression of Long-Chain Acyl-CoA Synthetase 5 Increases Fatty Acid Oxidation and Free Radical Formation While Attenuating Insulin Signaling in Primary Human Skeletal Myotubes," IJERPH, MDPI, vol. 16(7), pages 1-15, March.
    • Handle: RePEc:gam:jijerp:v:16:y:2019:i:7:p:1157-:d:218676
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    References listed on IDEAS

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    1. Nicholas Houstis & Evan D. Rosen & Eric S. Lander, 2006. "Reactive oxygen species have a causal role in multiple forms of insulin resistance," Nature, Nature, vol. 440(7086), pages 944-948, April.
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