Protecting the Diabetic Skeletal Muscle by Nampt Activation

项目摘要 糖尿病是美国和世界范围内的主要死亡原因，对 肌肉骨骼系统。不管血糖控制如何，骨骼肌中的糖尿病表现为 新陈代谢导致进行性骨骼肌丧失，功能衰退，快速型肌纤维萎缩， 对损伤和再生能力受损的敏感性增加。我们对这一建议的理解是 与代谢改变和骨骼肌风险增加相关的直接原因现象 糖尿病。我们已经发现，糖尿病会导致肌肉NADH水平显著升高，同时 耗尽的NAD储备。这种现象与肌肉功能下降和损伤直接相关。 基于我们在吡啶核苷酸和代谢调节领域的初步研究和专业知识，我们 假设糖尿病骨骼肌中NAD/NADH比率降低会导致肌肉中NAD/NADH的下降 功能，激活烟酰胺磷酸核糖转移酶(NAMPT)具有保护作用。主要目标 是开发NAMPT激活剂来保护骨骼肌免受糖尿病和其他代谢相关疾病的影响 综合症。为此，我们提出了两个具体目标。在特定目标1A下，我们将拯救胰岛素抵抗 糖尿病骨骼肌伴P7C3。我们将利用糖尿病小鼠模型来识别肌肉活动减少 且强度与NAMPT、NAD/NADH比值对功能改善的相关性。实验性的 方法将包括功能、生化和分子测量。这些实验将确定 NAD/NADH在糖尿病骨骼肌中的基础作用。特定目标1B将开发创新的 骨骼肌靶向P7C3纳米微粒给药系统。肉碱-P7C3颗粒将允许 体内给药和体外给药均有较高疗效。在具体目标2A下，我们将调查 P7C3抗糖尿病骨骼肌并发症的机制研究信号通路涉及 NAMPT-HNF1β-PPARα将使用肌肉特异性敲除小鼠模型来阐明HNF1βFlox 用HSAcre小鼠评价肝细胞核因子1-β(β)作为一种新的功能因子的主要作用 骨骼肌中的代谢调节剂。最后，在子目标2B中，我们将研究分子 南美普妥的药理作用及其靶向和识别sirt1、hnf1β及脂质的特异性 参与肌肉保护的信号媒介。总体而言，项目的完成将决定因果关系 NAMPT在糖尿病骨骼肌中的作用及其与新靶点HNF1β的关系 配合NAMPT，以最佳方式调节骨骼肌新陈代谢。

Project Summary Diabetes is a leading cause of death in the US and worldwide with deleterious consequences to the musculoskeletal system. Regardless of glycemic control, diabetes in skeletal muscle manifests with altered metabolism leading to progressive skeletal muscle loss, functional decline, fast-type myofiber atrophy, increased susceptibility to injury and impaired regeneration. The proposal we develop understanding for the direct causal phenomenon associated with altered metabolism and increased risk to skeletal muscle in diabetes. We have identified that diabetes causes significant elevation in muscle NADH levels along with depleted NAD+ reserves. This phenomenon directly associates with decreased muscle function and damage. Based on our preliminary studies and expertise in the area of pyridine nucleotides and metabolic regulation, we hypothesize that decreased NAD/NADH ratio in the diabetic skeletal muscle leads to decline in muscle function, and activation of nicotinamide phosphoribosyl transferase (Nampt) is protective. The major objective is to develop Nampt activators to protect skeletal muscles from diabetes and other metabolic-related syndromes. For this, we propose two specific aims. Under Specific Aim 1A, we will rescue insulin resistance in diabetic skeletal muscle with P7C3. We will utilize diabetic mouse model to identify decreased muscle activity and strength and the relevance of Nampt, NAD/NADH ratio for improvement of function. The experimental approach will include functional, biochemical and molecular measurements. These experiments will establish the fundamental role of NAD/NADH in diabetic skeletal muscle. Specific Aim 1B will develop the innovative skeletal muscle targeting P7C3 nano particle drug delivery system. The Carnitine-P7C3 particle will allow higher therapeutic efficacy for in vivo and in vitro delivery. Under Specific Aim 2A we will investigate the mechanistic basis of P7C3 against diabetic complications in skeletal muscle. The signaling pathway involving Nampt-HNF1β-PPARα will be elucidated using muscle specific knock out mouse models for HNF1βflox along with HSAcre mice to evaluate the chief role of hepatocyte nuclear factor 1-β (HNF1β) as a new functional metabolic modulator in skeletal muscles. Finally, in Sub aim 2B we will investigate the molecular pharmacology of Nampt and its specificity for targeting and identification of SIRT1, HNF1β along with lipid signaling mediators involved in muscle protection. Overall, completion of the project will determine the causal role of Nampt in diabetic skeletal muscle and unravel novel mechanisms with new targets HNF1β that co- orchestrate with Nampt to optimally regulate metabolism in skeletal muscle.