Regulation of Skeletal Muscle Anabolic Resistance in Obesity

骨骼肌对合成代谢刺激的抵抗，如营养素，胰岛素或阻力运动，是一个主要的 肥胖、老年和其他表现为胰岛素抵抗的疾病。因此， 据估计，美国有2600万成年人被诊断患有糖尿病，90-95% 2型糖尿病的患者。2型糖尿病的发病率是多少？ 预计到2050年将翻一番，因为所有人口统计数据中的肥胖率继续上升， 2型糖尿病患者的寿命更长。肌肉质量和功能的丧失会导致残疾 并且是死亡率的独立预测因子，这两者在肥胖期间都会加重。减少 功能促进不活动，这是肌肉萎缩，代谢不平衡， 降低胰岛素敏感性。胰岛素和营养素对骨骼肌的这些合成代谢作用可以 抑制由反调节激素和细胞因子，这往往是升高的肥胖。 然而，对有助于合成代谢的区别机制的理解有限。 随着肥胖症的发展和进展，骨骼肌质量的抵抗和损失。因此，目标 这项建议的一个重要目的是了解蛋白质在发育和DNA损伤中的作用 反应1（REDD 1）对调节骨骼肌适应的合成代谢刺激的影响 营养干预。有待检验的中心假设是，限制REDD 1的增加， 在肥胖期间的表达将增强骨骼肌的合成代谢作用和表型， 调节骨骼肌生长信号和自噬。使用新的条件性REDD 1敲除 小鼠模型结合营养过剩或限制，REDD 1对整体和组织的作用 肥胖症期间的表型和代谢将在目标1中确定。在目标2中，REDD 1 对合成代谢抵抗的作用。最后一个目标是研究REDD 1和自噬对合成代谢的影响。 肥胖时的抵抗力这项研究的结果将揭示一种创新的营养调节 肥胖症时骨骼肌的合成代谢作用和代谢机制， 操纵的蛋白质，导致新的和创新的方法来预防和治疗合成代谢 阻力

Skeletal muscle resistance to anabolic stimuli, such as nutrients, insulin, or resistance exercise, is a major problem for the obese, aged, and other conditions manifested by insulin resistance. Accordingly, there are an estimated 26 million adults in the United States who have been diagnosed with diabetes, 90–95% of which have type 2 diabetes. The population of individuals diagnosed and living with type 2 diabetes is projected to double by 2050, given that obesity rates continue to rise in all demographics and that individuals are living longer with type 2 diabetes. A loss of muscle mass and function promotes disability and are independent predictors of mortality, both of which are exacerbated during obesity. Reduced function promotes inactivity, which is a potent inducer of muscle atrophy, metabolic disequilibrium, and reduced insulin sensitivity. These anabolic effects of insulin and nutrients on skeletal muscle can be inhibited by counter regulatory hormones and cytokines, which are often elevated in the obesity. However, there is a limited understanding of the discriminate mechanisms that contribute to anabolic resistance and loss of skeletal muscle mass as obesity develops and progresses. Therefore, the objective of this proposal is to understand the role of the protein regulated in development and DNA damage responses 1 (REDD1) on the regulation of anabolic stimulation of skeletal muscle adaptation to long-term nutrient interventions. The central hypothesis to be tested is that limiting an increase in REDD1 expression during obesity will augment skeletal muscle anabolic action and phenotype through the regulation of skeletal muscle growth signaling and autophagy. Using a novel conditional REDD1 knockout mouse model in combination with nutrient excess or restriction, the role of REDD1 on whole and tissue phenotype and metabolism during obesity will be determined in Aim 1. In Aim 2 regulators of REDD1’s role on anabolic resistance. The last aim will examine the impact of REDD1 and autophagy on anabolic resistance during obesity. Findings from this research will reveal an innovative nutrient-regulated mechanism of anabolic action and metabolism in skeletal muscle during obesity that could be manipulated pharmacologically, resulting in new and innovative approaches to prevent and treat anabolic resistance.