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Studies have linked the development of sarcopenia to reductions in capillary vessel network density and suggest that such changes may partly account for the loss of skeletal muscle (SkM) mass and function. Thus, the interest in identifying and evaluating safe and effective candidate compounds that can stimulate angiogenesis. We previously reported on the capacity of (+)-epicatechin (+Epi) to reverse SkM atrophy and loss of function in aged rats. We also reported on the apparent angiogenic effect of +Epi in mouse brain cortex. However, no studies have evaluated the angiogenic potential of +Epi in SkM. Using 23 month old male rats, we evaluated the angiogenic effect of 8 weeks of 1 mg/kg/day oral treatment of +Epi on SkM (gastrocnemius). To identify underlying mechanisms, we evaluated the PI3K/eNOS pathway, as well as the expression of the angiogenic factors HIF1-α, VEGF and VEGFR2. Results demonstrate that + Epi stimulates increases in protein levels for HIF1-α (∼35%), VEGF (∼40%), VEGFR2 (∼25%), as well as CD31 (capillaries, ∼25%). Such effects were linked with the activation (phosphorylation) of PI3K (∼30%), eNOS (∼90%), VEGFR2 at T951 (∼90%) and T996 amino acid sites (∼110%). +Epi also stimulated increased synthesis of phosphatidylinositol trisphosphate (∼30%) and tetrahydrobiopterine (∼90%), as well as of nitric oxide (∼140% in gastrocnemius and ∼70% in plasma) and cyclic guanosine monophosphate (∼90%) in gastrocnemius and in plasma (∼40%). In summary, in aged rats oral treatment with +Epi stimulates SkM angiogenesis and such actions may partly account for the reversal of the deleterious effects of sarcopenia. [ABSTRACT FROM AUTHOR]

We examined in a rat model of Gulf War illness (GWI), the potential of (−)-epicatechin (Epi) to reverse skeletal muscle (SkM) atrophy and dysfunction, decrease mediators of inflammation and normalize metabolic perturbations. Male Wistar rats (n = 15) were provided orally with pyridostigmine bromide (PB) 1.3 mg/kg/day, permethrin (PM) 0.13 mg/kg/day (skin), DEET 40 mg/kg/day (skin) and were physically restrained for 5 min/day for 3 weeks. A one-week period ensued to fully develop the GWI-like profile followed by 2 weeks of either Epi treatment at 1 mg/kg/day by gavage (n = 8) or water (n = 7) for controls. A normal, control group (n = 15) was given vehicle and not restrained. At 6 weeks, animals were subjected to treadmill and limb strength testing followed by euthanasia. SkM and blood sampling was used for histological, biochemical and plasma pro-inflammatory cytokine and metabolomics assessments. GWI animals developed an intoxication profile characterized SkM atrophy and loss of function accompanied by increases in modulators of muscle atrophy, degradation markers and plasma pro-inflammatory cytokine levels. Treatment of GWI animals with Epi yielded either a significant partial or full normalization of the above stated indicators relative to normal controls. Plasma metabolomics revealed that metabolites linked to inflammation and SkM waste pathways were dysregulated in the GWI group whereas Epi, attenuated such changes. In conclusion, in a rat model of GWI, Epi partially reverses detrimental changes in SkM structure including modulators of atrophy, inflammation and select plasma metabolites yielding improved function. [ABSTRACT FROM AUTHOR]

There is evidence implicating oxidative stress (OS) as the cause of the deleterious effects of aging. In this study, we evaluated the capacity of the flavanol (-)-epicatechin (Epi) to reduce aging-induced OS and restore mitochondrial biogenesis, as well as, structural and functional endpoints in aged mice. Senile (S; 26-month-old) C57BL/6 male mice were randomly assigned to receive either water (vehicle) or 1mg/kg of Epi via oral gavage (twice daily) for 15 days. Young (Y; 6-month-old) mice were used as controls. In S brain, kidney, heart, and skeletal muscle (compared with Y animals) an increase in OS was observed as evidenced by increased protein-free carbonyls and decreased reduced glutathione levels as well as sirtuin 3, superoxide dismutase 2, catalase, thioredoxin and glutathione peroxidase protein levels. Well-recognized factors (eg, sirtuin 1) that regulate mitochondrial biogenesis and mitochondrial structure- and/or function-related endpoints (eg, mitofilin and citrate synthase) protein levels were also reduced in S organs. In contrast, the aging biomarker senescence-associated β-galactosidase was increased in S compared with Y animals, and Epi administration reduced levels towards those observed in Y animals. Altogether, these data suggest that Epi is capable of shifting the biology of S mice towards that of Y animals. [ABSTRACT FROM AUTHOR]

HF (heart failure) and T2D (Type 2 diabetes) associate with detrimental alterations in SkM (skeletal muscle) structure/function. We have demonstrated recently that (-)-ERC (epicatechin-rich cocoa) improves SkM mitochondrial structure [Taub, Ramirez-Sanchez, Ciaraldi, Perkins, Murphy, Naviaux, Hogan, Ceballos, Maisel, Henry et al. (2012) Clin. Trans. Sci. 5, 43-47]. We hypothesized that an improved mitochondrial structure may facilitate the reversal of detrimental alterations in sarcomeric microstructure. In a pilot study, five patients with HF and T2D consumed ERC for 3 months; treadmill testing [VO2max (maximum oxygen consumption)] and SkM biopsies were performed. Western blot analysis, immunohistochemistry and electron microscopy were used. We report severe perturbations in components of the DAPC (dystrophin-associated protein complex) as well as sarcomeric microstructure at baseline. ERC induced recovery/enhancement of DAPC protein levels, sarcomeric microstructure and, in a co-ordinated fashion, alterations in markers of SkM growth/differentiation consistent with myofibre regeneration. VO2max increased (~24%) but did not reach statistical significance. These initial results warrant further rigorous investigation, since the use of ERC (or pure epicatechin) may represent a safe and novel means of improving muscle function. [ABSTRACT FROM AUTHOR]

(-)-Epicatechin (Epi), a flavanol in cacao stimulates mitochondrial volume and cristae density and protein markers of skeletal muscle (SkM) mitochondrial biogenesis in mice. Type 2 diabetes mellitus (DM2) and heart failure (HF) are diseases associated with defects in SkM mitochondrial structure/function. A study was implemented to assess perturbations and to determine the effects of Epi-rich cocoa in SkM mitochondrial structure and mediators of biogenesis. Five patients with DM2 and stage II/III HF consumed dark chocolate and a beverage containing approximately 100 mg of Epi per day for 3 months. We assessed changes in protein and/or activity levels of oxidative phosphorylation proteins, porin, mitofilin, nNOS, nitric oxide, cGMP, SIRT1, PGC1α, Tfam, and mitochondria volume and cristae abundance by electron microscopy from SkM. Apparent major losses in normal mitochondria structure were observed before treatment. Epi-rich cocoa increased protein and/or activity of mediators of biogenesis and cristae abundance while not changing mitochondrial volume density. Epi-rich cocoa treatment improves SkM mitochondrial structure and in an orchestrated manner, increases molecular markers of mitochondrial biogenesis resulting in enhanced cristae density. Future controlled studies are warranted using Epi-rich cocoa (or pure Epi) to translate improved mitochondrial structure into enhanced cardiac and/or SkM muscle function. Clin Trans Sci 2012; Volume 5: 43-47 [ABSTRACT FROM AUTHOR]

Age-related muscle decline, when associated with obesity, leads to adverse outcomes with increased risks for falling, loss of independence, disability and risk of premature mortality. The aim of this study was to assess the potential beneficial effects of flavonoids in improving the age-/high-fat-diet-induced decrease in physical activity/capacity related to the onset of skeletal muscle decline. The effects of the administration of a cocoa beverage enriched with flavanols or pure (−)-epicatechin for 5 wk in a model of physical activity decline induced by the ingestion of a high-fat diet (60% fat) in middle-age mice were evaluated. The results showed that both products, the cocoa beverage enriched with flavanols and pure (−)-epicatechin, improved physical performance evaluated with the hang-wire, inverted-screen, and weight-lifting tests and dynamometry compared with the performance of the controls. The beverage and (−)-epicatechin increased the follistatin/myostatin ratio and increased the expression of myocyte enhancer factor 2A (MEF2A), suggesting an effect on molecular modulators of growth differentiation. Furthermore, the beverage and (−)-epicatechin decreased the expression of O-type fork-head transcription factor (FOXO1A) and muscle ring finger 1 (MURF1) markers of the skeletal muscle ubiquitin-proteasome degradation pathway. Image 1 [ABSTRACT FROM AUTHOR]

Skeletal muscle (SkM) is a highly dynamic tissue that responds to physiological adaptations or pathological conditions, and SkM mitochondria play a major role in bioenergetics, regulation of intracellular calcium homeostasis, pro-oxidant/antioxidant balance, and apoptosis. Flavonoids are polyphenolic compounds with the ability to modulate molecular pathways implicated in the development of mitochondrial myopathy. Therefore, it is pertinent to explore its potential application in conditions such as aging, disuse, denervation, diabetes, obesity, and cancer. To evaluate preclinical and clinical effects of flavonoids on SkM structure and function. We performed a systematic review of published studies, with no date restrictions applied, using PubMed and Scopus. The following search terms were used: "flavonoids" OR "flavanols" OR "flavones" OR "anthocyanidins" OR "flavanones" OR "flavan-3-ols" OR "catechins" OR "epicatechin" OR "(−)-epicatechin" AND "skeletal muscle." The studies included in this review were preclinical studies, clinical trials, controlled clinical trials, and randomized-controlled trials that investigated the influence of flavonoids on SkM health. Three authors, independently, assessed trials for the review. Any disagreement was resolved by consensus. The use of flavonoids could be a potential tool for the prevention of muscle loss. Their effects on metabolism and on mitochondria function suggest their use as muscle regulators. [ABSTRACT FROM AUTHOR]

Abstract: Sarcopenia is a notable and debilitating age-associated condition. Flavonoids are known for their healthy effects and limited toxicity. The flavanol (−)-epicatechin (Epi) enhances exercise capacity in mice, and Epi-rich cocoa improves skeletal muscle structure in heart failure patients. (−)-Epicatechin may thus hold promise as treatment for sarcopenia. We examined changes in protein levels of molecular modulators of growth and differentiation in young vs. old, human and mouse skeletal muscle. We report the effects of Epi in mice and the results of an initial proof-of-concept trial in humans, where muscle strength and levels of modulators of muscle growth were measured. In mice, myostatin and senescence-associated β-galactosidase levels increase with aging, while those of follistatin and Myf5 decrease. (−)-Epicatechin decreases myostatin and β-galactosidase and increases levels of markers of muscle growth. In humans, myostatin and β-galactosidase increase with aging while follistatin, MyoD and myogenin decrease. Treatment for 7 days with (−)-epicatechin increases hand grip strength and the ratio of plasma follistatin/myostatin. In conclusion, aging has deleterious effects on modulators of muscle growth/differentiation, and the consumption of modest amounts of the flavanol (−)-epicatechin can partially reverse these changes. This flavanol warrants its comprehensive evaluation for the treatment of sarcopenia. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]

Currently, there is great interest in identifying endogenous (i.e. physiological) stimulators of mitochondrial biogenesis (MB), in particular, those that may mediate the effects of exercise. The molecular size of the cacao flavanols (epicatechin and catechin) highly resembles that of sterols and epicatechin has been reported to activate cells surface receptors leading to the stimulation of MB in endothelial and skeletal muscle cells translating into enhanced exercise capacity. We therefore hypothesize, that epicatechin may be acting as a structural mimic of an as yet unknown sterol capable of stimulating MB. We developed a new synthetic process for obtaining enantiomerically pure preparations of (-)-epicatechin and (+)-epicatechin. Applying spatial analytics and molecular modeling, we found that the two isoforms of epicatechin, (-) and (+), have a structural resemblance to 11-β-hydroxypregnenolone, a sterol with no previously described biological activity. As reported in this proof-of-concept study performed in primary cultures of endothelial and muscle cells, 11-β-hydroxypregnenolone is one of the most potent inducers of MB as significant activity can be detected at femtomolar levels. The relative potency of (-)/(+)-epicatechin isoforms and on inducing MB correlates with their degree of spatial homology towards the 11-β-hydroxypregnenolone. On the basis of these results, the detailed in vivo characterization of the potential for these sterols to act as endogenous modulators of MB is warranted. [ABSTRACT FROM AUTHOR]