Epicatechin and derivatives to preserve muscle structure function in diabetes

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）线粒体的改变限制了组织的生长，从而促进了肌肉功能障碍。具体而言，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，该研究小组得到了为期1年的NIDDK种子R24提案（“靶向细胞生物能量学用于预防和治疗糖尿病”）的支持，该研究小组描述了可可中存在的初级黄烷醇(-)-表儿茶素（Epi）对线粒体相关终点的积极作用。因此，这类化合物的使用可以作为实现我们主要目标的有力工具，并为其治疗潜力提供证据。我们对小鼠和人类原代细胞的研究表明，Epi刺激SkM线粒体质量/体积，增加线粒体最大呼吸速率。此外，1 mg/kg BID Epi灌胃15天后，小鼠SkM功能、耐力、线粒体体积、嵴密度和毛细血管均有所增强。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，在该研究中，富Epi可可管理恢复了SkM（股四头肌）线粒体嵴密度，并增加了线粒体生物发生的多种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中断有关。事实上，在用富含Epi的可可进行治疗后，肌瘤组织得到了改善，肌肉生长/再生的标志物也得到了改善，包括肌肉生长抑制素、卵泡抑制素和MyoD等。通过我们的合作努力，我们还合成了更有效的外泌素异构体形式和活性在低nM范围内的新型衍生物。这些结果为将来使用Epi（和可申请专利的相关化合物）作为治疗DM2诱导的SkM相关病理的治疗剂铺平了道路，这也可能改善疾病概况。为了揭示这些反应的机制，我们将检验以下假设：目的1。假设：DM2的存在导致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：体外对线粒体结构/功能的刺激可恢复DM2诱导的SkM分化和生长潜力的丧失。目标3。假设：体内线粒体结构/功能的刺激逆转了DM2诱导的SkM生长和功能的丧失。该转化提案旨在进一步推动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，为DM2患者的相关临床试验的规划和实施提供严格的临床前结果。

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.