The Role of Intramuscular Lipids in Muscle Anabolic Resistance

肌内脂质在肌肉合成代谢抵抗中的作用

• 批准号: 9461483
• 负责人: Sue C Bodine
• 金额: $ 47.17万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9461483
• 关键词: Address; Attenuated; Biochemistry; Biology; Biophysics; Blood Vessels; Cardiovascular Diseases; Clinical; Cues; Data; Development; Diabetes Mellitus; Diet; Fatty Acids; Fatty acid glycerol esters; Female; Formulation; Growth; High Fat Diet; Imaging Techniques; Impairment; Incidence; Injury; Intake; Intramuscular; Knockout Mice; Lasers; Lead; Limb structure; Lipids; Magnetic Resonance Imaging; Measures; Metabolism; Modeling; Molecular; Mouse Strains; Movement; Mus; Muscle; Muscle Weakness; Muscle function; Muscular Atrophy; Obesity; Prevalence; Process; Production; Protein Biosynthesis; Proteins; Publishing; Raman Spectrum Analysis; Recovery; Research; Resistance; Role; Signal Transduction; Skeletal Muscle; Technology; Testing; Thermogenesis; Time; Translations; attenuation; base; blood glucose regulation; clinically relevant; diabetes risk; disorder risk; endoplasmic reticulum stress; falls; fatty acid metabolism; feeding; lipid metabolism; male; mechanical load; metabolic phenotype; muscle form; novel; prevent; public health relevance; response; saturated fat; ubiquitin-protein ligase

 DESCRIPTION (provided by applicant): Obesity and high-fat diets (HFD) increase the risk for disorders of skeletal muscle function including anabolic resistance, which is an inability to increase protein synthesis in response to feeding or growth cues. Anabolic resistance leads to the attenuation of muscle growth under conditions of increased loading, such as recovery from disuse and functional overload. The objective of this application is to examine the mechanisms by which a HFD and/or obesity reduces load-induced muscle growth in both male and female mice. Our recent findings reveal that in mice fed a HFD muscle growth in response to increased loading is significantly attenuated. These results have led to the formulation of our central hypothesis: the development of anabolic resistance in diet-induced obesity is related to an accumulation of intramuscular lipids and increased fatty acid intermediates leading to an increase in oxidative and endoplasmic reticulum (ER) stress, which inhibits anabolic signaling in response to increased loading. To address our hypothesis, we propose three specific aims that take advantage of unique differences in three mouse strains (C57BL/6J, MuRF1-/-, and ob/ob) and two load-induced growth models: functional overload and hind limb unloading/reloading. State of the art imaging techniques (7-T MRI, laser trapping Raman spectroscopy, and coherent anti-Stokes Raman spectroscopy) will be used to measure intramuscular lipid content and lipid droplet size, number, and composition. In Aim 1 we will test the hypothesis that increasing duration on a diet high in saturated fats, and not adiposity, leads to the development of anabolic resistance in male and female mice. In Aim 2 we will test the hypothesis that a HFD leads to an increase in intramyocellular lipids and the accumulation of fatty acid intermediates causing the development of anabolic resistance. In Aim 3 we will test the hypothesis that MuRF1-/- mice on a HFD have reduced storage of intramuscular lipids and a decrease in fatty acid intermediates, which prevents the development of anabolic resistance. This application is significant because it will lead to major advances in our understanding of the effects of obesity and diets high in saturated fats on the ability of muscle to respond to growth cues, which is clinically important because anabolic resistance leads to decreased mobility and independence, increases the likelihood of injuries and falls, and further increases the risk for diabetes mellitus and cardiovascular disease.

 描述（由申请人提供）：肥胖和高脂肪饮食（HFD）会增加骨骼肌功能紊乱的风险，包括合成代谢抵抗，即无法响应进食或生长线索而增加蛋白质合成。在负荷增加的情况下，例如从废用和功能超负荷中恢复，合成代谢阻力会导致肌肉生长减弱。本申请的目的是研究 HFD 和/或肥胖降低雄性和雌性小鼠负荷诱导的肌肉生长的机制。我们最近的研究结果表明，喂食 HFD 的小鼠肌肉生长对负荷增加的反应显着减弱。这些结果导致我们提出了中心假设：饮食诱导的肥胖中合成代谢抵抗的发展与肌内脂质的积累和脂肪酸中间体的增加有关，导致氧化和内质网（ER）应激增加，从而抑制合成代谢信号以响应负荷增加。为了解决我们的假设，我们提出了三个具体目标，利用三种小鼠品系（C57BL/6J、MuRF1-/-和ob/ob）的独特差异和两种负荷诱导的生长模型：功能超载和后肢卸载/重新加载。最先进的成像技术（7-T MRI、激光捕获拉曼光谱和相干反斯托克斯拉曼光谱）将用于测量肌内脂质含量和脂滴大小、数量和成分。在目标 1 中，我们将检验以下假设：增加高饱和脂肪饮食而非肥胖的持续时间会导致雄性和雌性小鼠出现合成代谢抵抗。在目标 2 中，我们将检验以下假设：HFD 会导致肌细胞内脂质增加和脂肪酸中间体积累，从而导致合成代谢抵抗的发展。在目标 3 中，我们将测试以下假设：服用 HFD 的 MuRF1-/- 小鼠减少了肌内脂质的储存和脂肪酸中间体的减少，从而防止了合成代谢抵抗的发展。这一应用意义重大，因为它将极大地促进我们对肥胖和高饱和脂肪饮食对肌肉响应生长信号的能力的影响的理解，这在临床上很重要，因为合成代谢阻力会导致活动能力和独立性下降，增加受伤和跌倒的可能性，并进一步增加患糖尿病和心血管疾病的风险。