Calcium/calmodulin dependent protein kinase (CaMK) activation induces mitochondrial biogenesis in response to increasing cytosolic calcium concentrations. Calcium leak from the ryanodine receptor is regulated by reactive oxygen species (ROS), which are increased with high-fat feeding. Therefore, we examined whether ROS-induced CaMKII-mediated signalling induced skeletal muscle mitochondrial biogenesis in selected models of lipid oversupply. In obese Zucker rats and in high fat-fed rodents, in which muscle mitochondrial content was upregulated, CaMKII phosphorylation was increased independent of changes in calcium uptake, as sarco(endo)plasmic (SR) reticulum Ca2+-ATPase (SERCA) protein expression or activity were not altered, implicating altered 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 ryanodine receptor while hydrogen peroxide induced SR calcium leak from the ryanodine receptor and activation of CaMKII. Moreover, administration of a mitochondrial-specific antioxidant (SkQ) prevented high-fat diet-induced phosphorylation of CaMKII as well as 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 the induction of mitochondrial biogenesis in response to excess lipid availability.
- INDUCED INSULIN-RESISTANCE
- MOUSE SKELETAL-MUSCLE
- PALMITATE OXIDATION
- ACID OXIDATION
Jain, S. S., Paglialunga, S., Vigna, C., Ludzki, A., Herbst, E. A., Lally, J. S., Schrauwen, P., Hoeks, J., Tupling, A. R., Bonen, A., & Holloway, G. P. (2014). High-Fat Diet-Induced Mitochondrial Biogenesis Is Regulated by Mitochondrial-Derived Reactive Oxygen Species Activation of CaMKII. Diabetes, 63(6), 1907-1913. https://doi.org/10.2337/db13-0816