Targeting of mitochondrial reactive oxygen species production does not avert lipid-induced insulin resistance in muscle tissue from mice.
OBJECTIVE
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
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.
Department of Human Biology, NUTRIM - School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, P.O. Box 616, 6200 MD, Maastricht, the Netherlands.
S
S
Paglialunga
Department of Human Biology, NUTRIM - School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, P.O. Box 616, 6200 MD, Maastricht, the Netherlands.
B
B
van Bree
Department of Human Biology, NUTRIM - School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, P.O. Box 616, 6200 MD, Maastricht, the Netherlands.
M
M
Bosma
Department of Nutrition, Food Science, Physiology and Toxicology, University of Navarra, Navarra, Spain.
M P
MP
Valdecantos
Grup Metabolisme Energètic i Nutrició, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Spain.
E
E
Amengual-Cladera
Department of Human Biology, NUTRIM - School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, P.O. Box 616, 6200 MD, Maastricht, the Netherlands.
J A
JA
Jörgensen
Department of Human Biology, NUTRIM - School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, P.O. Box 616, 6200 MD, Maastricht, the Netherlands.
D
D
van Beurden
Department of Toxicology, NUTRIM - School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands.
G J M
GJM
den Hartog
Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany.
D M
DM
Ouwens
Department of Toxicogenomics, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
J J
JJ
Briedé
Department of Human Biology, NUTRIM - School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, P.O. Box 616, 6200 MD, Maastricht, the Netherlands.
P
P
Schrauwen
Department of Human Biology, NUTRIM - School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, P.O. Box 616, 6200 MD, Maastricht, the Netherlands. j.hoeks@maastrichtuniversity.nl.
J
J
Hoeks
D000818:Animals; D004041:Dietary Fats / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000378:metabolism*; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010971:Plastoquinone / Q000031:analogs & derivatives* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*
C532038:10-(6'-plastoquinonyl)decyltriphenylphosphonium; D004041:Dietary Fats; D016166:Free Radical Scavengers; D007328:Insulin; D008055:Lipids; D017382:Reactive Oxygen Species; D005947:Glucose; D010971:Plastoquinone