Type 2 diabetes (T2D) and heart failure (HF) are associated with high levels of skeletal muscle (SkM) oxidative stress (OS). Health benefits attributed to flavonoids have been ascribed to antioxidation. However, for flavonoids with similar antioxidant potential, end-biological effects vary widely suggesting other mechanistic venues for reducing OS. Decreases in OS may follow the modulation of key regulatory pathways including antioxidant levels (e.g. glutathione) and enzymes such as mitochondrial superoxide dismutase (SOD2) and catalase.
We examined OS-related alterations in SkM in T2D/HF patients (as compared vs. healthy controls) and evaluated the effects of three-month treatment with (−)-epicatechin (Epi) rich cocoa (ERC). To evidence Epi as the mediator of the improved OS profile we examined the effects of pure Epi (vs. water) on SkM OS regulatory systems in a mouse model of insulin resistance and contrasted results vs. normal mice.
There were severe alterations in OS regulatory systems in T2D/HF SkM as compared with healthy controls. Treatment with ERC induced recovery in glutathione levels and decreases in the nitrotyrosilation and carbonylation of proteins. With treatment, key transcriptional factors translocate into the nucleus leading to increases in SOD2 and catalase protein expression and activity levels. In insulin resistant mice, there were alterations in muscle OS and pure Epi replicated the beneficial effects of ERC found in humans.
Major perturbations in SkM OS can be reversed with ERC in T2D/HF patients. Epi likely mediates such effects and may provide an effective means to treat conditions associated with tissue OS.
Abbreviations:T2D (type 2 diabetes), HF (heart failure), SkM (skeletal muscle), OS (oxidative stress), SOD2 (superoxide dismutase-2), Epi ((−)-epicatechin), ERC ((−)-epicatechin rich cocoa), HFD (high fat diet), DNP (2,4-dinitrophenyldrazone), WB (western blotting), PGC1α (peroxisome proliferator-activated receptor gamma coactivator 1-α), SIRT (sirtuin), GAPDH (glyceraldehyde 3-phosphate dehydrogenase), S6RP (S6 ribosomal protein), FOXO1 (forkhead box protein O1), IP (immunoprecipitation), ROS (reactive oxygen species)
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Published online: July 19, 2013
Accepted: June 30, 2013
Received in revised form: June 17, 2013
Received: January 3, 2013
☆Acknowledgment of grant support: This study was supported by NIH AT4277, HL43617, P60-MD000220, and DK92154 and grants from the Medical Research Service, Department of Veterans Affairs, VA San Diego Healthcare System and an unrestricted gift from Cardero Therapeutics Inc.
© 2013 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.