Mechanisms of lipid-induced bioenergetic stress in muscle

脂质诱导肌肉生物能应激的机制

• 批准号: 10409823
• 负责人: DEBORAH M MUOIO
• 金额: $ 59万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10409823
• 关键词: ATP Hydrolysis; Acute; Acyl Coenzyme A; Age; Aging; Area; Bioenergetics; Biological Assay; Biological Markers; Blood; Blood Glucose; Butyrates; Carbon; Cardiac; Cardiometabolic Disease; Catabolic Process; Catabolism; Clinical; Complex; Consumption; Diabetes Mellitus; Diagnostic; Disease; Electron Transport; Electrons; Energy Metabolism; Energy Transfer; Enzymes; Event; Exercise Tolerance; Exercise stress test; Fasting; Fatty Acids; Free Energy; Functional disorder; Grant; Health; Heart; Heart Mitochondria; Heart failure; Hereditary Disease; Homeostasis; Human; Impairment; In Vitro; Institutes; Intermittent fasting; Ketones; Kinetics; Laboratories; Link; Lipids; Mass Spectrum Analysis; Mediator of activation protein; Membrane Potentials; Metabolic; Metabolic Diseases; Metabolic stress; Metabolism; Methods; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Modeling; Mole the mammal; Molecular; Molecular Profiling; Mus; Muscle; Muscle Mitochondria; Myocardial dysfunction; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Normal Cell; Nutrient; Obesity; Organ; Organ failure; Outcome; Oxidation-Reduction; Oxidoreductase; Pathway interactions; Phosphorylation; Physiological; Physiology; Play; Population; Post-Translational Protein Processing; Potential Energy; Prediabetes syndrome; Process; Proteomics; Regimen; Reporting; Research Personnel; Resistance; Role; Route; Signal Transduction; Skeletal Muscle; Stress; Stress Tests; Technology; Testing; Thermodynamics; Tissues; Work; acylcarnitine; age related; base; cancer cachexia; cardiometabolism; diagnostic assay; diagnostic platform; exercise intolerance; fatty acid oxidation; insight; long chain fatty acid; metabolomics; mitochondrial dysfunction; multiple omics; multiplex assay; novel therapeutic intervention; nutrition related genetics; oxidation; phosphoproteomics; respiratory; response; stem; tool

Abstract Our work in the area of mitochondrial function, energy homeostasis and metabolomics has led us to discover a remarkably strong association between adverse cardiometabolic outcomes and tissue/blood levels of acylcarnitine (AC) conjugates. These metabolites derive from acyl-CoA intermediates of fuel catabolism and permit mitochondrial export of excess carbons. For the past decade, our laboratory has remained keenly committed to answering a crucial question: What is this AC signature telling us about the interplay between mitochondria and metabolic disease? The current proposal aims to test the hypothesis that AC accumulation reflects a bottleneck in the fatty acid oxidation (FAO) pathway that diminishes mitochondrial power and efficiency. This prediction stems from unique insights gained via the application of a new mitochondrial diagnostics platform developed by our laboratory during the previous grant cycle. In simple terms, our assays serve as an in vitro “stress test” that evaluates how well a given population of mitochondria, fueled by specific mixtures of carbon substrates, responds to a graded energetic challenge. We have been combining this platform with mass spectrometry-based metabolomics, proteomics and 13C metabolic flux analysis to evaluate mitochondrial remodeling and corresponding changes in respiratory power and efficiency in response to a variety of nutritional and genetic maneuvers. New and exciting findings suggest that AC accumulation reflects a critical thermodynamic vulnerability in the mitochondrial FAO pathway, and thereby serves as a signal of bioenergetic stress, en route to compromised bioenergetics and impending tissue/organ failure. Moreover, our preliminary studies suggest mitochondria resident in untrained skeletal muscles and failing hearts are especially vulnerable to this lipid-induced “traffic jam”; and that ketones are uniquely able to circumvent the roadblock to defend cellular energetics in settings of metabolic stress. Accordingly, we also aim to test the hypothesis that ketone oxidation plays an essential role in permitting the salutary mitochondrial and metabolic adaptations known to occur in response to regimens of intermittent fasting.

抽象的 我们在线粒体功能、能量稳态和代谢组学领域的工作引领我们 发现不良心脏代谢结果与 酰基肉碱 (AC) 缀合物的组织/血液水平这些代谢物源自酰基辅酶 A。 燃料分解代谢的中间体并允许线粒体输出多余的碳。 十年来，我们的实验室一直致力于回答一个关键问题：什么是 这个 AC 告诉我们线粒体和代谢之间的相互作用 目前的提议旨在检验 AC 积累反映了疾病的假设 脂肪酸氧化 (FAO) 途径中的瓶颈，会降低线粒体能量并 这一预测源于通过应用新方法获得的独特见解。 我们实验室在上一个资助周期开发的线粒体诊断平台。 简而言之，我们的检测作为体外“压力测试”，评估给定的效果 线粒体群体，由特定的碳底物混合物提供能量，对分级反应做出反应 我们一直在将该平台与基于质谱的技术相结合。 用于评估线粒体重塑的代谢组学、蛋白质组学和 13C 代谢流分析 以及响应各种变化的呼吸功率和效率的相应变化 新的令人兴奋的发现表明AC积累。 线粒体FAO途径中一个关键的热力学脆弱性，从而服务于 作为生物能量应激的信号，在生物能量受损和即将发生的情况下 此外，我们的初步研究表明线粒体存在于未经训练的细胞中。 骨骼肌和衰竭的心脏特别容易受到这种脂质引起的“交通堵塞”的影响； 酮具有独特的能力，能够绕过障碍，保护环境中的细胞能量学 因此，我们还旨在检验酮氧化发挥作用的假设。 在允许有益的线粒体和代谢适应方面发挥着重要作用 是对间歇性禁食方案的反应而发生的。

项目成果

Diabetes: The good in fat.

糖尿病：脂肪的好处。

• 发表时间: 2014-12-04
• 影响因子: 64.8
• 作者: Muoio, Deborah M;Newgard, Christopher B
• 通讯作者: Newgard, Christopher B

Comprehensive metabolic modeling of multiple 13C-isotopomer data sets to study metabolism in perfused working hearts.

多个 13C 同位素异构体数据集的综合代谢模型，用于研究灌注工作心脏的代谢。

• 发表时间: 2016
• 作者: Crown, Scott B;Kelleher, Joanne K;Rouf, Rosanne;Muoio, Deborah M;Antoniewicz, Maciek R
• 通讯作者: Antoniewicz, Maciek R

HDAC3 sets the timer on muscle fuel switching.

HDAC3 设置肌肉燃料切换计时器。

• 发表时间: 2017-02-07
• 影响因子: 82.9
• 作者: Muoio; Deborah M
• 通讯作者: Deborah M

Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis.

代谢组定量性状位点 (mQTL) 作图暗示泛素蛋白酶体系统在心血管疾病发病机制中的作用。

• 发表时间: 2015-11
• 影响因子: 4.5
• 作者: Kraus, William E;Muoio, Deborah M;Stevens, Robert;Craig, Damian;Bain, James R;Grass, Elizabeth;Haynes, Carol;Kwee, Lydia;Qin, Xuejun;Slentz, Dorothy H;Krupp, Deidre;Muehlbauer, Michael;Hauser, Elizabeth R;Gregory, Simon G;Newgard, Christophe
• 通讯作者: Newgard, Christophe

Long-echo time MR spectroscopy for skeletal muscle acetylcarnitine detection.

用于骨骼肌乙酰肉碱检测的长回波时间磁共振波谱。

• 发表时间: 2014-11
• 作者: Lindeboom, Lucas;Nabuurs, Christine I;Hoeks, Joris;Brouwers, Bram;Phielix, Esther;Kooi, M Eline;Hesselink, Matthijs K C;Wildberger, Joachim E;Stevens, Robert D;Koves, Timothy;Muoio, Deborah M;Schrauwen, Patrick;Schrauwen
• 通讯作者: Schrauwen