High-Fat Diet–Induced Mitochondrial Biogenesis Is Regulated by Mitochondrial-Derived Reactive Oxygen Species Activation of CaMKII
- Swati S. Jain1,
- Sabina Paglialunga1,
- Chris Vigna2,
- Alison Ludzki1,
- Eric A. Herbst1,
- James S. Lally1,
- Patrick Schrauwen3,
- Joris Hoeks3,
- A. Russ Tupling2,
- Arend Bonen1 and
- Graham P. Holloway1⇑
- 1Department of Human Health & Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada
- 2Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada
- 3Department of Human Biology, Maastricht University, Maastricht, the Netherlands
- Corresponding author: Graham P. Holloway, .
Calcium/calmodulin-dependent protein kinase (CaMK) activation induces mitochondrial biogenesis in response to increasing cytosolic calcium concentrations. Calcium leak from the ryanodine receptor (RyR) is regulated by reactive oxygen species (ROS), which is increased with high-fat feeding. We examined whether ROS-induced CaMKII-mediated signaling induced skeletal muscle mitochondrial biogenesis in selected models of lipid oversupply. In obese Zucker rats and high-fat–fed rodents, in which muscle mitochondrial content was upregulated, CaMKII phosphorylation was increased independent of changes in calcium uptake because sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) protein expression or activity was not altered, implicating altered sarcoplasmic reticulum (SR) calcium leak in the activation of CaMKII. In support of this, we found that high-fat feeding increased mitochondrial ROS emission and S-nitrosylation of the RyR, whereas hydrogen peroxide induced SR calcium leak from the RyR and activation of CaMKII. Moreover, administration of a mitochondrial-specific antioxidant, SkQ, prevented high-fat diet–induced phosphorylation of CaMKII and the induction of mitochondrial biogenesis. Altogether, these data suggest that increased mitochondrial ROS emission is required for the induction of SR calcium leak, activation of CaMKII, and induction of mitochondrial biogenesis in response to excess lipid availability.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0816/-/DC1.
J.S.L. is currently affiliated with the Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
See accompanying article, p. 1831.
- Received May 22, 2013.
- Accepted February 3, 2014.
- © 2014 by the American Diabetes Association.
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