STARS-SRF Pathway- A Novel Regulator of Muscle Metabolism and Insulin Resistance

描述（由申请人提供）：2型糖尿病（T2D）在美国已达到流行病的比例，影响约8.3%的人口，并造成巨大的个人、公共卫生和经济损失。不幸的是，细胞和分子异常赋予遗传和环境决定的糖尿病风险仍然没有完全理解。因此，寻找与T2D风险相关的基因和途径对于开发新的和改进的预防和治疗方法至关重要。Patti实验室最近的研究发现了一种新的、意想不到的T2D患者骨骼肌基因表达模式。这种模式包括由血清反应因子（SRF）及其上游调节蛋白STARS（Rho依赖性信号的横纹肌激活剂）调节的基因表达增加。此外，STARS表达与胰岛素抵抗呈负相关。重要的是，这种模式也存在于基于家族史的疾病风险中，可能将其与T2D风险联系起来（Jin和Patti，JCI 2011）。初步数据表明，STARS-SRF途径可以稳健地调节肌肉胰岛素抵抗和全身代谢，有助于T2D病理生理学。具体地，STARS-SRF的激活诱导胰岛素抗性并减少脂肪酸氧化，而SRF的抑制或STARS表达的减少改善线粒体氧化代谢并增加肌管中胰岛素刺激的葡萄糖转运。此外，STARS基因敲除小鼠对饮食诱导的肥胖和葡萄糖耐受不良具有抵抗力，这可能是通过增加运动能力和能量消耗实现的。该提案的重点是测试创新假设，即STARS-SRF的激活在促进胰岛素抵抗中起着关键作用，并且抑制该途径是T2D的新治疗方法。提出了三个具体目标来验证这些假设，并阐明介导这些作用的分子机制：（1）通过评估过表达STARS的肌管和肌肉特异性STARS转基因小鼠中的胰岛素作用、葡萄糖转运和氧化代谢，确定STARS-SRF激活的代谢后果。(2)通过详细分析STARS基因敲除小鼠和STARS转基因小鼠原代肌管中线粒体质量/功能和胰岛素信号转导，确定STARS-SRF调节氧化代谢和胰岛素敏感性的机制。由于初步数据表明STARS-SRF抑制激活AMP激酶，我们将测试STARS对氧化代谢的影响是否通过AMP激酶介导。(3)利用特异性SRF抑制剂来剖析在培养的肌管中介导改善胰岛素作用和氧化代谢的途径，并确定这些抑制剂是否可以类似地改善肥胖和T2D小鼠体内的葡萄糖代谢和能量消耗。

DESCRIPTION (provided by applicant): Type 2 diabetes (T2D) has reached epidemic proportions in the United States, affecting an estimated 8.3% of the population and inflicting enormous personal, public health, and financial tolls. Unfortunately, the cellular and molecular abnormalities that confer genetic and environmentally- determined diabetes risk remain incompletely understood. Thus, finding genes and pathways linked to T2D risk is essential for developing new and improved approaches to prevention and treatment. Recent studies from the Patti Lab have identified a novel, unexpected pattern of gene expression in skeletal muscle from human patients with established T2D. This pattern includes increased expression of genes regulated by serum response factor (SRF) and its upstream regulatory protein STARS (striated muscle activator of Rho-dependent signaling). Moreover, STARS expression correlates inversely with insulin resistance. Importantly, this pattern is also present in those at risk for disease based on family history, potentially linking this to risk for T2D (Jin and Patti, JCI 2011) Preliminary data indicate that the STARS-SRF pathway can robustly regulate muscle insulin resistance and systemic metabolism, contributing to T2D pathophysiology. Specifically, activation of STARS-SRF induces insulin resistance and reduces fatty acid oxidation, while inhibition of SRF or reduced STARS expression improves mitochondrial oxidative metabolism and increases insulin- stimulated glucose transport in myotubes. Moreover, STARS-null mice are resistant to diet-induced obesity and glucose intolerance, potentially via increased exercise capacity and energy expenditure. This proposal focuses on testing the innovative hypothesis that activation of STARS-SRF plays a pivotal role in promoting insulin resistance, and that inhibition of this pathway is a novel therapeutic approach for T2D. Three specific aims are proposed to test these hypotheses and to elucidate molecular mechanisms mediating these effects: (1) To determine the metabolic consequences of STARS-SRF activation, by assessing insulin action, glucose transport, and oxidative metabolism in myotubes overexpressing STARS and in muscle-specific STARS transgenic mice. (2) To identify mechanisms by which STARS-SRF modulates oxidative metabolism and insulin sensitivity by detailed analysis of mitochondrial mass/function & insulin signaling in primary myotubes from both STARS-null and STARS-transgenic mice. Since preliminary data indicate that STARS-SRF inhibition activates AMP kinase, we will test whether STARS effects on oxidative metabolism are mediated via AMP kinase. (3) To utilize specific SRF inhibitors to dissect pathways mediating improved insulin action and oxidative metabolism in cultured myotubes, and determine whether these inhibitors can similarly improve glucose metabolism and energy expenditure in vivo, in mice with obesity and T2D.