Intermuscular adipose tissue (IMAT): protagonist in sarcopenia and insulin resistance in humans

摘要 肌间脂肪组织(IMAT)存在于肌纤维之间和肌筋膜下，是 与胰岛素抵抗和骨质疏松症呈正相关。尚不清楚的是，IMAT如何促进减少 肌肉大小、力量和胰岛素敏感性。因此，迫切需要解决这些知识上的差距。 因为，在满足这一需要之前，IMAT作为预防/治疗II型的干预措施的目标的可能性 糖尿病和骨量减少不太可能实现。这个项目的总体目标是量化 IMAT相对于内脏(VAT)和皮下脂肪组织(SAT)的分泌组，并测定 IMAT分泌体引起炎症的相对效力，并减少收缩蛋白的表达 以及体外的胰岛素敏感性。我们的中心假设是IMAT分泌组促进肌肉 炎症，并降低肌肉质量、力量和胰岛素敏感性。这背后的理由是 建议澄清IMAT是如何促进肌肉大小、力量和胰岛素敏感性下降的 能够开发新的治疗干预措施来预防或治疗骨质疏松症和2型糖尿病。至 为了实现我们的目标，我们提出了两个具体目标：具体目标1.测定IMAT和内脏脂肪 与皮下脂肪组织相比，组织的分泌体在代谢上是不利的 人类。我们的初步数据显示，IMAT分泌炎性细胞因子和二十烷类化合物类似于 增值税。我们的工作假设是IMAT和VAT分泌炎性细胞因子、脂肪因子、二十烷类化合物， 与SAT相比，促进代谢功能障碍的细胞外基质蛋白。我们建议 糖尿病前期和2型瘦身、肥胖者IMAT、VAT和SAT分泌组的测定 2糖尿病。肌肉质量、力量和胰岛素敏感性将使用mri、等速测力仪进行测量。 和高胰岛素/正血糖钳夹。将对IMAT分泌组的组成进行比较 与SAT和VAT相关，并与供者胰岛素敏感性、力量和肌肉质量相关，以揭示潜力 IMAT改变肌肉功能的机制。具体目标2.确立国际货币基金组织的效力 分泌体引起炎症反应，降低胰岛素敏感性和收缩蛋白 体外表达。基于强大的初步数据，我们的工作假设是IMAT和增值税 分泌体会增加炎症反应，降低胰岛素敏感性和收缩蛋白 相对于SAT中的表达式。体外反应将按组进行比较， IMAT分泌组将与细胞培养结果的变化相关，以揭示其潜在的机制 行动。拟议的研究具有创新性，因为它代表了对现状的实质性偏离 通过直接在人类身上采集IMAT样本。这一贡献将是重大的，因为IMAT从来没有 从人类采集的，用于详细研究，并将揭示肌肉间脂肪组织作为一种新的治疗方法 目标是对抗骨质疏松症和2型糖尿病。

Abstract Intermuscular adipose tissue (IMAT) exists between muscle fibers and under the muscle fascia, and is positively related to insulin resistance and sarcopenia. What is not known is how IMAT promotes decreased muscle size, strength, and insulin sensitivity. Thus, there is a critical need to address these gaps in knowledge because, until that need is met, the potential for IMAT as a target for interventions that prevent/treat type 2 diabetes and sarcopenia is unlikely to be realized. The overall objective for this project is to quantify the secretome of IMAT relative to visceral (VAT) and subcutaneous adipose tissue (SAT), and determine the relative potency of the IMAT secretome to cause inflammation, and decreased contractile protein expression and insulin sensitivity in vitro. Our central hypothesis is that the IMAT secretome promotes muscle inflammation, and decreases muscle mass, strength, and insulin sensitivity. The rationale that underlies this proposal is that clarifying how IMAT promotes decreased muscle size, strength, and insulin sensitivity will enable development of novel therapeutic interventions to prevent or treat sarcopenia and type 2 diabetes. To achieve our objective, we propose two specific aims: Specific Aim 1. Determine that IMAT and visceral adipose tissue have a secretome that is metabolically adverse when compared to subcutaneous adipose tissue in humans. Our preliminary data show that IMAT secretes inflammatory cytokines and eicosanoids similar to VAT. Our working hypothesis is that IMAT and VAT secrete inflammatory cytokines, adipokines, eicosanoids, and extracellular matrix proteins that promote metabolic dysfunction when compared to SAT. We propose to measure the secretome of IMAT, VAT and SAT in lean, obese, and obese individuals with pre-diabetes and type 2 diabetes. Muscle mass, strength, and insulin sensitivity will be measured using MRI, isokinetic dynamometry and hyperinsulinemic/ euglycemic clamps, respectively. Components of the IMAT secretome will be compared to SAT and VAT, and correlated to donor insulin sensitivity, strength, and muscle mass to reveal potential mechansims by which IMAT alters muscle function. Specific Aim 2. Establish the potency of the IMAT secretome to cause an inflammatory response, and decrease insulin sensitivity and contractile protein expression in vitro. Based on strong preliminary data, our working hypothesis is that IMAT and VAT secretome will increase the inflammatory response, and decrease insulin sensitivity and contractile protein expression relative to that from SAT. In vitro responses will be compared by group, and constituents of the IMAT secretome will be correlated to the change in cell culture outcomes to reveal potential mechanisms of action. The proposed research is innovative because it represents a substantive departure from the status quo by directly sampling IMAT in humans. This contribution will be significant because IMAT has never been collected from humans for detailed studies, and will reveal intermuscular adipose tissue as a new therapeutic target to combat sarcopenia and type 2 diabetes.