Redox Biology and Muscle Insulin Sensitivity

氧化还原生物学和肌肉胰岛素敏感性

• 批准号: 8891410
• 负责人: P Darrell Neufer
• 金额: $ 35.16万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-17 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8891410
• 关键词: Address; Antioxidants; Bioenergetics; Biology; Buffers; Cell physiology; Chronic; Cysteine; Data; Development; Diabetes Mellitus; Diet; Dietary Fats; Electron Transport; Electrons; Engineering; Environment; Epidemic; Equilibrium; Etiology; Event; Fatty acid glycerol esters; Fire - disasters; Generations; Goals; Health; Hydrogen Peroxide; In Vitro; Insulin; Insulin Resistance; Intake; Interphase Cell; Kinetics; Lead; Link; Lipids; Measures; Mediating; Mediator of activation protein; Membrane; Metabolic; Mitochondria; Modeling; Mus; Muscle; Muscle Development; NADPH Oxidase; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Nutritional; Obesity; Oxidation-Reduction; Peroxisome Proliferator-Activated Receptors; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Prevention; Prevention strategy; Preventive; Process; Production; Protein Serine/Threonine Phosphatase; Proteome; Publishing; Pyruvate Dehydrogenase Complex; Regulation; Relative (related person); Respiratory System; Role; Series; Signal Transduction; Signaling Protein; Site; Skeletal Muscle; Stress; Superoxides; System; Transgenic Mice; Transgenic Organisms; Work; genetic approach; glucose uptake; in vivo; insight; insulin sensitivity; insulin signaling; loss of function; mouse model; oxidation; pressure; prevent; protective effect; research study; respiratory; response; treatment strategy; voltage

DESCRIPTION (provided by applicant): The underlying mechanism responsible for the development of diet-induced insulin resistance in skeletal muscle remains unresolved. Decreased insulin sensitivity is a key factor in the etiology of type 2 diabetes and, as such, identifying the underlying mechanism of insulin resistance is critical to devising appropriate prevention and treatment strategies. Recent evidence indicates high dietary fat intake increases mitochondrial hydrogen peroxide production and emission in muscle, shifting the intracellular redox environment to a more oxidized state. Blocking the hydrogen peroxide emission through the use of mitochondrial targeted antioxidants prevents the shift in cellular redox environment and preserves insulin sensitivity, providing evidence the mitochondrial respiratory system senses and initiates a counterbalance response to cellular nutritional overload. The long-term objectives of this project are to define the underlying bioenergetics mechanisms regulating mitochondrial hydrogen peroxide production/emission, to determine the impact on and integration with cellular redox systems, and to decipher the mechanism by which redox signaling networks link to the control of insulin sensitivity. The specific goals of this project ae to determine if flux through �-oxidation is a primary factor governing mitochondrial hydrogen peroxide emission, cellular redox state, and insulin sensitivity; to determine the mechanism(s) regulating hydrogen peroxide production/emission by the pyruvate dehydrogenase complex; and to determine the potential role of hydrogen peroxide induced redox regulation of phosphatase activity as a potential mediator of diet-induced insulin resistance. State-of-the-art mitochondrial function analyses as well as gain- and loss-of-function mouse models will be employed to address these goals. It is anticipated these studies will reveal new insights regarding the underlying mechanism by which metabolic imbalance leads to insulin resistance in skeletal muscle, providing the framework for devising appropriately targeted prevention and/or treatment strategies.

描述（由申请人提供）：导致骨骼肌中饮食诱导的胰岛素抵抗发生的根本机制仍未解决。胰岛素敏感性降低是 2 型糖尿病病因学的关键因素，因此，需要确定其根本机制。胰岛素抵抗对于制定适当的预防和治疗策略至关重要。最近的证据表明，高膳食脂肪摄入会增加肌肉中线粒体过氧化氢的产生和排放，从而将细胞内氧化还原环境转变为更加氧化的状态。通过使用线粒体靶向抗氧化剂来阻止过氧化氢的排放，可以防止细胞氧化还原环境的变化并保持胰岛素敏感性，为线粒体呼吸系统感知并启动对细胞营养超负荷的平衡反应提供证据。该项目的长期目标是。定义调节线粒体过氧化氢产生/排放的潜在生物能机制，确定对细胞氧化还原系统的影响和整合，并破译氧化还原信号网络与胰岛素敏感性控制联系的机制。该项目的具体目标是确定β-氧化通量是否是控制线粒体过氧化氢排放、细胞氧化还原状态和胰岛素敏感性的主要因素；确定丙酮酸脱氢酶复合物调节过氧化氢产生/排放的机制；并确定过氧化氢诱导的氧化还原调节磷酸酶活性作为饮食诱导的胰岛素抵抗的潜在介质的潜在作用以及最先进的线粒体功能分析以及增益和增益。功能丧失小鼠模型将用于实现这些目标，预计这些研究将揭示有关代谢失衡导致骨骼肌胰岛素抵抗的潜在机制的新见解，为设计有针对性的预防和/或提供框架。或治疗策略。

项目成果

Mitochondrial therapy improves limb perfusion and myopathy following hindlimb ischemia.

线粒体治疗可改善后肢缺血后的肢体灌注和肌病。

• 发表时间: 2016-08
• 影响因子: 5
• 作者: Ryan, Terence E;Schmidt, Cameron A;Alleman, Rick J;Tsang, Alvin M;Green, Thomas D;Neufer, P Darrell;Brown, David A;McClung, Joseph M
• 通讯作者: McClung, Joseph M

Rapid Repression of ADP Transport by Palmitoyl-CoA Is Attenuated by Exercise Training in Humans: A Potential Mechanism to Decrease Oxidative Stress and Improve Skeletal Muscle Insulin Signaling.

人体运动训练可减弱棕榈酰辅酶 A 对 ADP 转运的快速抑制：减少氧化应激和改善骨骼肌胰岛素信号传导的潜在机制。

• 发表时间: 2015-08
• 影响因子: 7.7
• 作者: Ludzki, Alison;Paglialunga, Sabina;Smith, Brennan K;Herbst, Eric A F;Allison, Mary K;Heigenhauser, George J;Neufer, P Darrell;Holloway, Graham P
• 通讯作者: Holloway, Graham P

Flux through mitochondrial redox circuits linked to nicotinamide nucleotide transhydrogenase generates counterbalance changes in energy expenditure.

通过与烟酰胺核苷酸转氢酶相关的线粒体氧化还原回路的通量会产生能量消耗的平衡变化。

• 发表时间: 2020
• 作者: Smith, Cody D;Schmidt, Cameron A;Lin, Chien;Fisher;Neufer, P Darrell
• 通讯作者: Neufer, P Darrell

Direct real-time quantification of mitochondrial oxidative phosphorylation efficiency in permeabilized skeletal muscle myofibers.

透化骨骼肌肌纤维中线粒体氧化磷酸化效率的直接实时定量。

• 发表时间: 2016
• 作者: Lark, Daniel S;Torres, Maria J;Lin, Chien;Ryan, Terence E;Anderson, Ethan J;Neufer, P Darrell
• 通讯作者: Neufer, P Darrell

The anticancer agent doxorubicin disrupts mitochondrial energy metabolism and redox balance in skeletal muscle.

• DOI: 10.1016/j.freeradbiomed.2013.08.191
• 发表时间: 2013-12
• 期刊: Free radical biology & medicine
• 影响因子: 7.4
• 作者: Gilliam, Laura A. A.;Fisher-Wellman, Kelsey H.;Lin, Chien-Te;Maples, Jill M.;Cathey, Brook L.;Neufer, P. Darrell
• 通讯作者: Neufer, P. Darrell