Oxidative Stress Regulation in Skeletal Muscle Under Clinical Metabolic Strain
In patients with heart failure and type 2 diabetes, (-)-epicatechin-rich cocoa modulated oxidative-stress regulators in skeletal muscle, supporting an effect on redox biology in clinically relevant tissue.
Skeletal Muscle Structure, Regeneration, and Cardiometabolic Health
This clinical study found structural sarcomere abnormalities in skeletal muscle from patients with heart failure and type 2 diabetes, and reported restorative effects after (-)-epicatechin-rich cocoa intake.
Mitochondrial Biogenesis, Muscle Regeneration, and Human Neuromuscular Disease
In adults with Becker muscular dystrophy, (-)-epicatechin increased markers of mitochondrial biogenesis and muscle regeneration, suggesting a potentially relevant biological response in a human neuromuscular condition.
Beneficial Effects of Flavonoids on Skeletal Muscle Health: A Systematic Review and Meta-Analysis
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.
(−)-Epicatechin reduces muscle waste after complete spinal cord transection in a murine model: role of ubiquitin–proteasome system
The skeletal muscle mass reduces 30–60% after spinal cord injury, this is mostly due to protein degradation through ubiquitin–proteasome system. In this work, we propose that the flavanol (−)-epicatechin, due its widespread biological effects on muscle health, can prevent muscle mass decrease after spinal cord injury. Thirty-six female Long Evans rats were randomized into 5 groups: (1) Spinal cord injury 7 days, (2) Spinal cord injury + (−)-epicatechin 7 days, (3) Spinal cord injury 30 days, (4) Spinal cord injury + (−)-epicatechin 30 days and (5) Sham (Only laminectomy). Hind limb perimeter, muscle cross section area, fiber cross section area and ubiquitin–proteasome system protein expression together with total protein ubiquitination were assessed. At 30 days Spinal cord injury group lost 49.52 ± 2.023% of muscle cross section area (−)-epicatechin treated group lost only 24.28 ± 15.45% being a significant difference. Ubiquitin–proteasome markers showed significant changes. FOXO1a increased in spinal cord injury group vs Sham (−)-epicatechin reduced this increase. In spinal cord injury group MAFbx increased significantly vs Sham but decrease in (−)-epicatechin treatment group at 30 days. At 7 and 30 days MuRF1 increased in the spinal cord injury and decreased in the (−)-epicatechin group. The global protein ubiquitination increases after spinal cord injury, epicatechin treatment induce a significant decrease in protein ubiquitination. These results suggest that (−)-epicatechin reduces the muscle waste after spinal cord injury through down regulation of the ubiquitin–proteasome system.
(-)-Epicatechin improves mitochondrial-related protein levels and ameliorates oxidative stress in dystrophic δ-sarcoglycan null mouse striated muscle
Muscular dystrophies (MDs) are a group of heterogeneous genetic disorders characterized by progressive striated muscle wasting and degeneration. Although the genetic basis for many of these disorders has been identified, the exact mechanism of disease pathogenesis remains unclear. The presence of oxidative stress (OS) is known to contribute to the pathophysiology and severity of the MD. Mitochondrial dysfunction is observed in MD, and probably represents an important determinant of increased OS. Experimental antioxidant therapies have been implemented with the aim of protecting against disease progression, but results from clinical trials have been disappointing. In this study, we explored the capacity of the cacao flavonoid (-)-epicatechin (Epi) to mitigate OS by acting as a positive regulator of mitochondrial structure/function endpoints and redox balance control systems in skeletal and cardiac muscles of dystrophic, δ-sarcoglycan (δ-SG) null mice. Wild-type or δ-SG null 2.5-month-old male mice were treated via oral gavage with either water (controls) or Epi (1 mg·kg(-1) , twice daily) for 2 weeks. The results showed significant normalization of total protein carbonylation, recovery of the glutathione/oxidized glutathione ratio and enhanced superoxide dismutase 2, catalase and citrate synthase activities with Epi treatment. These effects were accompanied by increases in the protein levels of thioredoxin, glutathione peroxidase, superoxide dismutase 2, catalase, and mitochondrial endpoints. Furthermore, we found decreases in heart and skeletal muscle fibrosis, accompanied by an improvement in skeletal muscle function, with treatment. These results warrant further investigation of Epi as a potential therapeutic agent to mitigate MD-associated muscle degeneration.
PXRは、骨格筋(-)-epicatechin 標的である
(-)-Epicatechin EC）は、心血管機能障害のリスク低減、代謝調節、骨格筋（SkM）のパフォーマンス向上、および骨格筋細胞の分化誘導など、数多くの生物学的効果を示しているフラバノールである。これまでに報告されているECの受容体分子では、ECが骨格筋に及ぼす作用を説明しきれていない。 我々は、ECとステロイド骨格との構造的類似性に基づき、プレグナンX受容体（PXR）がこれらの特性を満たし得ると仮説を立てた。また、PXRの活性化はECによって誘導されるものと同様の効果をもたらすと考えた。この仮説を実証するために、我々は：1) インシリコ戦略を用いてECとマウスPXRとの相互作用の可能性を解析し、2) PXRを単離するためのEC親和性カラムを開発し、 3) マウス筋芽細胞（C2C12細胞）において、PXRの特異的阻害剤であるケトコナゾールによるEC誘導性PXR核移行の阻害を評価し、4) マウスPXRの活性化因子としてのECの効果を、シトクロム3a11（Cyp3a11）遺伝子およびミオゲニンタンパク質の発現調節を評価することで解析した。(-)-Epicatechin これを活性化し、PXRの核内移行を促進し、Cyp3a11の発現を増加させ、ミオゲニン発現の増加を通じてC2C12細胞の分化を促進する。これらの結果は、ECが示す骨格筋への作用におけるPXRの関与の可能性を分析するための、今後の研究の基礎となり得る。