Epicatechin and derivatives to preserve muscle structure function in diabetes

表儿茶素及其衍生物可保护糖尿病患者的肌肉结构功能

基本信息

批准号：
8820260
负责人：
Robert Roy Henry
金额：
$ 34.49万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-10 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8820260
关键词：
Adverse effects Area Bioenergetics Biogenesis Biological Preservation Biology Cacao Plant Capillarity Cardiovascular Diseases Cell Proliferation Cells Clinical Trials Cocoa Powder Collaborations Crista ampullaris Dependence Deposition Diabetes Mellitus Diet Differentiation and Growth Disease Epidemic Exercise Fatty Acids Fatty acid glycerol esters Flavanol Follistatin Functional disorder Future Gene Silencing Glucose Goals Growth Health Heart failure Human In Vitro Insulin Resistance Intervention Isomerism Laboratories Link Lipids Mediator of activation protein Mitochondria Mitochondrial Crista Monoclonal Antibody R24 Mus Muscle Muscle Fibers Muscle Mitochondria Muscle function National Institute of Diabetes and Digestive and Kidney Diseases Natural regeneration Non-Insulin-Dependent Diabetes Mellitus Organelles Pathology Patients Physiology Play Prediabetes syndrome Prevention Proteins Publishing Research Resources Role Sampling Sarcomeres Science Seeds Skeletal Muscle Small Interfering RNA Structure System Testing Therapeutic Therapeutic Agents Wild Type Mouse cell growth cellular targeting density epicatechin functional restoration human subject improved in vivo mouse model muscle regeneration muscular structure myostatin novel pre-clinical quadriceps muscle respiratory response skeletal muscle differentiation skeletal muscle growth tool treadmill training

项目摘要

DESCRIPTION (provided by applicant): Our major hypothesis is that type 2 diabetes mellitus (DM2) induced alterations in skeletal muscle (SkM) mitochondria limit tissue growth and thus, facilitate muscle dysfunction. Specifically, this project will characterize DM2 induced perturbations in SkM mitochondria and their relationship with changes in mediators of muscle growth and differentiation. We intend to demonstrate that the preservation and/or enhancement of mitochondria structure/function will improve SkM growth and consequently, exercise capacity. Currently supported by a 1 year NIDDK seed R24 proposal ("Targeting cellular bioenergetics for the prevention and treatment of diabetes") this research team has characterized the positive effects of the primary flavanol present in cacao, (-)-epicatechin (Epi) on mitochondria related endpoints. Thus, the use of this class of compounds can serve as a powerful tool to pursue our major objective and generate evidence for their therapeutic potential. Our studies in mice and primary human cells demonstrate that Epi, stimulates SkM mitochondrial mass/volume and increases maximal mitochondrial respiratory rate. Further, mice treated with 1 mg/kg BID Epi by gavage for 15 days demonstrate enhanced SkM function, endurance, mitochondrial volume, cristae density and capillarity. We recently published the results of a study performed in heart failure DM2 patients in which Epi rich cocoa administration restored SkM (quadriceps) mitochondrial cristae density and increased protein and activity levels of multiple indicators of mitochondria biogenesis. We have also documented at baseline, severe perturbations in SkM structure and sarcomere organization. Interestingly, perturbations in mitochondrial biogenesis are linked to disruptions in muscle regeneration and differentiation. Indeed, following treatment with Epi rich cocoa sarcomere organization was improved as well as markers of muscle growth/regeneration including myostatin, follistatin and MyoD amongst others. Through our collaborative efforts, we have also synthetized more potent Epi isomer forms and novel derivatives active in the low nM range. These results pave the way for the future use of Epi (and patentable related compounds) as therapeutic agents for the treatment DM2 induced SkM related pathologies which are also likely to improve disease profile. To reveal the mechanisms responsible for these responses, we will test the following hypotheses: Aim 1. Hypothesis: The presence of DM2 leads to perturbations in SkM mitochondria structure/function, which adversely impacts regulators of growth and differentiation. Aim 2. Hypothesis: The in vitro stimulation of mitochondria structure/function restores DM2 induced loss of SkM differentiation and growth potential. Aim 3. Hypothesis: The in vivo stimulation of mitochondria structure/function reverses DM2 induced loss of SkM growth and function. This translational proposal is to further the R24 supported ongoing collaboration of Epi biology, diabetology and muscle physiology experts to provide rigorous pre-clinical results to be used for the planning and implementation of relevant clinical trials in DM2 patients.

描述（由申请人提供）：我们的主要假设是 2 型糖尿病 (DM2) 诱导骨骼肌 (SkM) 线粒体的改变限制组织生长，从而促进肌肉功能障碍。具体来说，该项目将表征 DM2 诱导的 SkM 线粒体扰动及其与肌肉生长和分化介质变化的关系。我们打算证明线粒体结构/功能的保存和/或增强将改善 SkM 的生长，从而提高运动能力。目前得到为期 1 年的 NIDDK 种子 R24 提案（“针对预防和治疗糖尿病的细胞生物能量学”）的支持，该研究小组已经描述了可可中主要黄烷醇 (-)-表儿茶素 (Epi) 对线粒体的积极影响相关端点。因此，使用此类化合物可以作为实现我们的主要目标并为其治疗潜力提供证据的有力工具。我们对小鼠和原代人类细胞的研究表明，Epi 可刺激 SkM 线粒体质量/体积并增加最大线粒体呼吸频率。此外，用 1 mg/kg BID Epi 灌胃处理 15 天的小鼠表现出 SkM 功能、耐力、线粒体体积、嵴密度和毛细血管功能增强。我们最近发表了一项在心力衰竭 DM2 患者中进行的研究结果，其中富含 Epi 的可可恢复了 SkM（股四头肌）线粒体嵴密度，并增加了线粒体生物发生的多个指标的蛋白质和活性水平。我们还记录了基线时 SkM 结构和肌节组织的严重扰动。有趣的是，线粒体生物发生的扰动与肌肉再生和分化的破坏有关。事实上，在使用富含 Epi 的可可进行治疗后，肌节组织以及肌肉生长/再生的标志物（包括肌生长抑制素、卵泡抑素和 MyoD 等）均得到改善。通过我们的共同努力，我们还合成了更有效的表观异构体形式和低 nM 范围内活性的新型衍生物。这些结果为未来使用 Epi（和可专利的相关化合物）作为治疗 DM2 诱导的 SkM 相关病理的治疗剂铺平了道路，这也可能改善疾病状况。为了揭示这些反应的机制，我们将测试以下假设：目标 1.假设：DM2 的存在会导致 SkM 线粒体结构/功能的扰动，从而对生长和分化的调节因子产生不利影响。目标 2. 假设：线粒体结构/功能的体外刺激可恢复 DM2 诱导的 SkM 分化和生长潜力的丧失。目标 3. 假设：线粒体结构/功能的体内刺激可逆转 DM2 诱导的 SkM 生长和功能丧失。该转化提案旨在进一步推进 R24 支持的 Epi 生物学、糖尿病学和肌肉生理学专家之间的持续合作，提供严格的临床前结果，用于规划和实施 DM2 患者的相关临床试验。