Regulation of reactive oxygen species (ROS) production by high-fat diet in skeletal muscle mitochondria

Tuesday, October 25, 2011 — Poster Session II
Noon – 2:00 p.m.	Natcher Conference Center	NIDDK	OXIDSTRESS-7

Authors

• Y Li
• V Periwal

Abstract

Insulin resistance (IR) induced by high-fat (HF) diet is correlated with elevated ROS levels. However, the underlying mechanism is unclear. The therapeutic importance of a mechanistic understanding of this mechanism cannot be over-stated. In this study, a mathematical model of skeletal muscle mitochondrial metabolism was developed. This model consists of the essential reaction/pathways in mitochondria. Mitochondrial responses to various substrates can be investigated. This model was validated firstly to compare model simulations with experimental data of muscle derived from normal diet. Several alterative hypotheses were further tested by perturbing parameters associated with ROS balance to investigate regulatory mechanism of HF on ROS. Model simulations can fit the ROS emission rate from mitochondria, estimated by the net ROS production for each substrate under normal diet condition. By enhancing the ROS production with increased parameters (e.g., ~400% increased for pyruvate), model simulation also can match well the data of skeletal muscle derived with HF diet. Complete inhibition of scavenging enzymes activity also can lead to the dramatic increase of ROS emission (~30% for pyruvate). Therefore, elevated ROS is most likely due to the increased ROS production induced by HF. The scavenging enzymes may also play an important role in maintaining ROS balance.

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