Targeting of mitochondrial reactive oxygen species production does not avert lipid-induced insulin resistance in muscle tissue from mice.

S. Paglialunga, B.W. van Bree, M. Bosma, M. P. Valdecantos, E. Amengual Cladera, J.A. Jorgensen, D. Van Beurden, G.J.M. den Hartog, DM. Ouwens, J.J. Briedé, P. Schrauwen, J. Hoeks*

*Corresponding author for this work

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Abstract

AIMS/HYPOTHESIS: High-fat, high-sucrose diet (HF)-induced reactive oxygen species (ROS) levels are implicated in skeletal muscle insulin resistance and mitochondrial dysfunction. Here we investigated whether mitochondrial ROS sequestering can circumvent HF-induced oxidative stress; we also determined the impact of any reduced oxidative stress on muscle insulin sensitivity and mitochondrial function. METHODS: The Skulachev ion (plastoquinonyl decyltriphenylphosphonium) (SkQ), a mitochondria-specific antioxidant, was used to target ROS production in C2C12 muscle cells as well as in HF-fed (16 weeks old) male C57Bl/6 mice, compared with mice on low-fat chow diet (LF) or HF alone. Oxidative stress was measured as protein carbonylation levels. Glucose tolerance tests, glucose uptake assays and insulin-stimulated signalling were determined to assess muscle insulin sensitivity. Mitochondrial function was determined by high-resolution respirometry. RESULTS: SkQ treatment reduced oxidative stress in muscle cells (-23% p < 0.05), but did not improve insulin sensitivity and glucose uptake under insulin-resistant conditions. In HF mice, oxidative stress was elevated (56% vs LF p < 0.05), an effect completely blunted by SkQ. However, HF and HF+SkQ mice displayed impaired glucose tolerance (AUC HF up 33%, p < 0.001; HF+SkQ up 22%; p < 0.01 vs LF) and disrupted skeletal muscle insulin signalling. ROS sequestering did not improve mitochondrial function. CONCLUSIONS/INTERPRETATION: SkQ treatment reduced muscle mitochondrial ROS production and prevented HF-induced oxidative stress. Nonetheless, whole-body glucose tolerance, insulin-stimulated glucose uptake, muscle insulin signalling and mitochondrial function were not improved. These results suggest that HF-induced oxidative stress is not a prerequisite for the development of muscle insulin resistance.
Original languageEnglish
Pages (from-to)2759-2768
Number of pages10
JournalDiabetologia
Volume55
Issue number10
DOIs
Publication statusPublished - Oct 2012

Keywords

  • Antioxidant treatment
  • High-fat high-sucrose diet
  • Insulin resistance
  • Oxidative stress
  • Reactive oxygen species
  • SkQ
  • HUMAN SKELETAL-MUSCLE
  • FATTY-ACID OXIDATION
  • PLASTOQUINONE DERIVATIVES
  • INTERRUPT EXECUTION
  • IN-VIVO
  • ROS GENERATION
  • LIFE-SPAN
  • STRESS
  • DYSFUNCTION
  • RESPIRATION

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