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

Hyo-Bum Kwak, Tracey L. Woodlief, Thomas D. Green, Julie H. Cox, Robert C. Hickner, P. Darrell Neufer and Ronald N. Cortright
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Hyo-Bum Kwak: Department of Physiology, East Carolina University, Greenville, NC 27858, USA
Tracey L. Woodlief: Department of Kinesiology, East Carolina University, Greenville, NC 27858, USA
Thomas D. Green: Department of Physiology, 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
Ronald N. Cortright: Department of Physiology, East Carolina University, Greenville, NC 27858, USA

IJERPH, 2019, vol. 16, issue 7, 1-15

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.

Keywords: ACSL-5; fatty acid oxidation; insulin signaling; mitochondria; ROS; skeletal muscle (search for similar items in EconPapers)
JEL-codes: I I1 I3 Q Q5 (search for similar items in EconPapers)
Date: 2019
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