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（DM 2）诱导的骨骼肌（SkM）线粒体改变限制了组织生长，从而促进了肌肉功能障碍。具体而言，该项目将表征DM 2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/功能的保留和/或增强将改善SkM生长，从而提高运动能力。目前，在一项为期1年的NIDDK种子R24提案（“靶向细胞生物能量学预防和治疗糖尿病”）的支持下，该研究小组已经表征了可可中主要黄烷醇（-）-表儿茶素（Epi）对线粒体相关终点的积极影响。因此，这类化合物的使用可以作为一个强大的工具，以追求我们的主要目标，并为他们的治疗潜力产生证据。我们在小鼠和原代人类细胞中的研究表明，Epi刺激SkM线粒体质量/体积并增加最大线粒体呼吸速率。此外，通过管饲法用lmg/kg BID Epi处理15天的小鼠显示出增强的SkM功能、耐力、线粒体体积、嵴密度和毛细作用。我们最近发表了在心力衰竭DM 2患者中进行的一项研究的结果，其中富含Epi的可可管理恢复了SkM（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中断有关。事实上，在用富含Epi的可可处理后，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）得到改善。 通过我们的合作努力，我们还合成了更有效的Epi异构体形式和在低nM范围内具有活性的新型衍生物。这些结果为将来使用Epi（和可专利的相关化合物）作为治疗剂用于治疗DM 2诱导的SkM相关病理铺平了道路，这也可能改善疾病概况。为了揭示这些反应的机制，我们将测试以下假设：目的1。假设：DM 2的存在导致SkM线粒体结构/功能的干扰，从而对生长和分化的调节因子产生不利影响。目标二。假设：线粒体结构/功能的体外刺激恢复了DM 2诱导的SkM分化和生长潜力的丧失。目标3：假设：线粒体结构/功能的体内刺激逆转了DM 2诱导的SkM生长和功能丧失。这项翻译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的持续合作，以提供严格的临床前结果，用于DM 2患者相关临床试验的规划和实施。

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.