Abstract
Background
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.
Methods
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.
Results
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.
Conclusions
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)Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to International Journal of CardiologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Chocolate consumption and cardiometabolic disorders: systematic review and meta-analysis.BMJ. 2011; 343: d4488
- Relationship of electrochemical oxidation of catechins on their antioxidant activity in microsomal lipid peroxidation.Chem Pharm Bull (Tokyo). Jun 2001; 49: 747-751
- Potential of phenolic antioxidants.Acta Chim Slov. 2010; 57: 263-271
- Consumption of flavonoid-rich foods and increased plasma antioxidant capacity in humans: cause, consequence, or epiphenomenon?.Free Radic Biol Med. Dec 15 2006; 41: 1727-1746
- Epicatechin ingested via cocoa products reduces blood pressure in humans: a nonlinear regression model with a Bayesian approach.Am J Clin Nutr. Jun 2012; 95: 1365-1377
- (−)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans.Proc Natl Acad Sci U S A. Jan 24 2006; 103: 1024-1029
- The stereochemical configuration of flavanols influences the level and metabolism of flavanols in humans and their biological activity in vivo.Free Radic Biol Med. Jan 15 2011; 50: 237-244
- Intake of dietary procyanidins does not contribute to the pool of circulating flavanols in humans.Am J Clin Nutr. Apr 2012; 95: 851-858
- Free radicals in the physiological control of cell function.Physiol Rev. Jan 2002; 82: 47-95
- Positive and negative regulation of insulin signaling by reactive oxygen and nitrogen species.Physiol Rev. Jan 2009; 89: 27-71
- Cocoa flavonoids up-regulate antioxidant enzyme activity via the ERK1/2 pathway to protect against oxidative stress-induced apoptosis in HepG2 cells.J Nutr Biochem. Mar 2009; 21: 196-205
- Greater propensity of diabetic myocardium for oxidative stress after myocardial infarction is associated with the development of heart failure.J Mol Cell Cardiol. Oct 2005; 39: 657-665
- Regulation of oxidative stress and cardioprotection in diabetes mellitus.Curr Cardiol Rev. Nov 2008; 4: 251-258
- (−)-Epicatechin enhances fatigue resistance and oxidative capacity in mouse muscle.J Physiol. Sep 15 2011; 589: 4615-4631
- Alterations in skeletal muscle indicators of mitochondrial structure and biogenesis in patients with type 2 diabetes and heart failure: effects of epicatechin rich cocoa.Clin Transl Sci. Feb 2012; 5: 43-47
- Diabetic cardiomyopathy revisited.Circulation. Jun 26 2007; 115: 3213-3223
- Effects of combining simvastatin with rosiglitazone on inflammation, oxidant stress and ambulatory blood pressure in patients with the metabolic syndrome: the SIROCO study.Diabetes Obes Metab. Feb 2012; 14: 181-186
- Angiotensin II inhibits endothelial cell motility through an AT1-dependent oxidant-sensitive decrement of nitric oxide availability.Arterioscler Thromb Vasc Biol. Jul 1 2003; 23: 1218-1223
- A diet rich in cocoa attenuates N-nitrosodiethylamine-induced liver injury in rats.Food Chem Toxicol. Oct 2009; 47: 2499-2506
- Protection of human HepG2 cells against oxidative stress by cocoa phenolic extract.J Agric Food Chem. Sep 10 2008; 56: 7765-7772
- Procyanidin B2 and a cocoa polyphenolic extract inhibit acrylamide-induced apoptosis in human Caco-2 cells by preventing oxidative stress and activation of JNK pathway.J Nutr Biochem. Dec 2011; 22: 1186-1194
- Short- and long-term effects of (−)-epicatechin on myocardial ischemia–reperfusion injury.Am J Physiol Heart Circ Physiol. Aug 2008; 295: H761-H767
- Identification, quantification, and functional aspects of skeletal muscle protein-carbonylation in vivo during acute oxidative stress.J Proteome Res. May 2010; 9: 2516-2526
- Metformin, arterial function, intima–media thickness and nitroxidation in metabolic syndrome: the mefisto study.Clin Exp Pharmacol Physiol. Aug. 2008; 35: 895-903
- Montmorency cherry juice reduces muscle damage caused by intensive strength exercise.Med Sci Sports Exerc. Aug 2011; 43: 1544-1551
- Role for oxidative stress in the regeneration of islet beta cells?.J Investig Med. Jan 2004; 52: 45-49
- Oxidative stress and diabetic complications.Circ Res. Oct 29 2010; 107: 1058-1070
- Endurance exercise as a countermeasure for aging.Diabetes. Nov 2008; 57: 2933-2942
- Antioxidant effects of cocoa and cocoa products ex vivo and in vivo: is there evidence from controlled intervention studies?.Curr Opin Clin Nutr Metab Care. Nov 2010; 13: 737-742
- Cocoa-enriched diet enhances antioxidant enzyme activity and modulates lymphocyte composition in thymus from young rats.J Agric Food Chem. Aug 8 2007; 55: 6431-6438
- Hypothalamic Sirt1 regulates food intake in a rodent model system.PLoS One. 2009; 4: e8322
- Effects of the phenolic contents of Mauritian endemic plant extracts on promoter activities of antioxidant enzymes.Free Radic Res. Nov 2003; 37: 1215-1224
- Changes in antioxidant endogenous enzymes (activity and gene expression levels) after repeated red wine intake.J Agric Food Chem. Aug 12 2009; 57: 6578-6583
- Antioxidative effects of exercise training in patients with chronic heart failure: increase in radical scavenger enzyme activity in skeletal muscle.Circulation. Apr 12 2005; 111: 1763-1770
- Dietary epicatechin promotes survival of obese diabetic mice and Drosophila melanogaster.J Nutr. Jun 2011; 141: 1095-1100
- The paradox of oxidative stress and exercise with advancing age.Exerc Sport Sci Rev. Apr 2011; 39: 68-76
Article info
Publication history
Published online: July 19, 2013
Accepted:
June 30,
2013
Received in revised form:
June 17,
2013
Received:
January 3,
2013
Footnotes
☆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.
Identification
Copyright
© 2013 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
