Epicatechin and derivatives to preserve muscle structure function in diabetes

描述(申请人提供)：我们的主要假设是2型糖尿病(DM2)导致骨骼肌(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。具体地说，这个项目将表征DM2诱导的SKM线粒体的扰动，以及它们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/或增强将促进SKM的生长，从而提高运动能力。该研究小组目前得到了一项为期一年的NIDDK SEED R24提案(“针对细胞生物能量用于糖尿病的预防和治疗”)的支持，该研究团队表征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影响。因此，这类化合物的使用可以作为一种强大的工具来实现我们的主要目标，并为其治疗潜力提供证据。我们在小鼠和原代人类细胞上的研究表明，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，Bid Epi 1 mg/kg灌胃15天的小鼠表现出增强的SKM功能、耐力、线粒体体积、嵴密度和毛细血管。我们最近公布了在心力衰竭DM2患者中进行的一项研究结果，在该研究中，富含可可的Epi可以恢复SKM(股四头肌)线粒体脊密度，并增加线粒体生物发生的多个指标的蛋白质和活性水平。我们还在基线上记录了SKM结构和肌节组织的严重扰动。有趣的是，线粒体生物发生的干扰与肌肉再生和分化的中断有关。事实上，在用富含可可的EPI治疗后，肌节组织以及肌肉生长/再生的标志包括肌肉生长抑制素、卵泡抑素和MyoD等都得到了改善。通过我们的共同努力，我们还合成了更有效的表面异构体和活性在低NM范围内的新型衍生物。这些结果为Epi(和可申请专利的相关化合物)未来用作治疗DM2引起的SKM相关病理的治疗剂铺平了道路，这些病理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产生不利影响。目的2.假说：体外刺激线粒体结构/功能可恢复DM2诱导的SKM分化和生长潜能的丧失。目的3.假设：体内对线粒体结构/功能的刺激可逆转DM2诱导的SKM生长和功能丧失。这项翻译建议是为了促进R24支持的EPI生物学、糖尿病和肌肉生理学专家正在进行的合作，以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。

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.