Role of Skeletal Muscle Mitochondrial Supercomplexes in Exercise Intolerance
骨骼肌线粒体超级复合物在运动不耐受中的作用
基本信息
- 批准号:10292886
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-01 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:Activities of Daily LivingAerobicAgonistAnimalsArchitectureAreaBindingBlood flowCardiac OutputCell LineCell RespirationChronicChronic DiseaseComplexCrista ampullarisDNA Sequence AlterationDataDyspneaElectron TransportElectron Transport Complex IIIExerciseExercise TherapyExercise ToleranceExhibitsFatigueFiberFoundationsFunctional disorderGenerationsHeart failureHumanImpairmentIncidenceIndividualInterventionInvestigationMediatingMediator of activation proteinMedicalMetabolicMitochondriaMitochondrial DiseasesModelingMolecularMolecular WeightMuscleMuscle FibersMuscle MitochondriaMuscle functionOPA1 genePatientsPerformancePeripheralPeroxisome Proliferator-Activated ReceptorsPharmacologyPharmacotherapyPhysical activityPopulationPotassium ChannelPre-Clinical ModelProductionProteinsPulmonary HypertensionQuality of lifeRattusReactive Oxygen SpeciesRegulationReportingRespirationRespiratory physiologyRoleSamplingSignal TransductionSkeletal MuscleSpeedStructureTestingVO2maxcomplex IVexercise capacityexercise intoleranceexercise trainingfunctional disabilityhemodynamicsimprovedmilitary veteranmortalitymuscle hypertrophynew therapeutic targetnovelnovel therapeuticspre-clinicalpreclinical studytargeted treatmenttherapeutically effectivetreadmill
项目摘要
ABSTRACT
Pulmonary hypertension is associated with poor quality of life, impaired functional tolerance and limitation of
physical activity. Despite optimal available therapy for PH, patients report fatigue, decreased functional
capacity, and worsening quality of life. Exercise intolerance (i.e. reduced VO2 max) is associated with reduced
skeletal muscle (SkM) mitochondrial function and cellular respiration. Recent studies have demonstrated that
changes in organization of electron transport chain complexes can significantly alter mitochondrial respiration
and energy production. Binding of individual electron transport chain complexes into large molecular weight
supercomplexes (SC) increases respiration efficiency, reduces damaging ROS, and improves ATP production.
SC can consist of complex I and multiple units of complex III and IV in direct association to allow direct electron
transfer. In preliminary studies, we have found that SkM in rats with PH have greatly reduced I/III/IV
supercomplex assembly and this is associated with reduced VO2 max determined by maximal treadmill
exercise capacity. Our central hypothesis is that reduction in mitochondrial SC in SkM contributes to exercise
intolerance in PH, and that increasing SC can alleviate PH-induced SkM dysfunction. We will test this
hypothesis using a well-established rat model of pulmonary hypertension that recapitulates the
pathophysiological aspects as well as exercise intolerance observed in patients with PH. In Aim 1, we will
evaluate PH-induced changes in SkM mitochondrial SC formation and associated changes in respiratory
function, mitochondrial content, and cristae architecture in a preclinical PH model and PH patients. In addition
we will verify these changes are indeed present in human SkM samples from PH patients. In Aim 2, we will
determine molecular mechanisms underlying altered mitochondrial function and SC assembly in isolated SkM
fibers and differentiated primary SkM myotubes from control and PH animals Finally in Aim 3, we will
determine if increasing mitochondrial supercomplex formation in SkM by exercise or drug therapy results in
improved functional capacity (i.e. VO2 max). These will be the first studies to evaluate the role of mitochondrial
SC in exercise intolerance associated with chronic medical condition such as PH, and the first studies to
directly target SC assembly to alleviate SkM dysfunction.
摘要
肺动脉高压与生活质量差、功能耐受性受损和肺动脉高压限制相关。
体力活动。尽管有最佳的PH治疗方法,但患者报告疲劳、功能下降
能力,生活质量下降。运动不耐受(即最大摄氧量降低)与
骨骼肌(SkM)线粒体功能和细胞呼吸。最近的研究表明,
电子传递链复合体结构的变化可显著改变线粒体呼吸
和能源生产。单个电子传递链复合物结合成大分子量
超复合物(SC)增加呼吸效率,减少破坏性ROS,并提高ATP的生产。
SC可以由复合物I和复合物III和IV的多个单元直接缔合以允许直接电子传递到复合物I。
转移在初步研究中,我们发现SkM在PH大鼠中大大降低了I/III/IV
超复杂的组装,这与最大跑步机确定的最大摄氧量降低有关
运动能力我们的中心假设是,减少线粒体SC在SkM有助于运动
增加SC可减轻PH引起的SkM功能障碍。我们将测试这个
假设使用一个完善的大鼠肺动脉高压模型,概括了
病理生理方面以及运动不耐受观察PH患者。在目标1,我们将
评估PH诱导的SkM线粒体SC形成的变化和呼吸系统的相关变化
在临床前PH模型和PH患者中的功能、线粒体含量和嵴结构。此外
我们将证实这些变化确实存在于PH患者的人SkM样品中。在目标2中,我们将
确定分离的SkM中线粒体功能和SC组装改变的分子机制
纤维和分化的初级SkM肌管从控制和PH动物最后在目标3中,我们将
确定通过运动或药物治疗增加SkM中线粒体超复合物的形成是否会导致
改善功能容量(即VO 2 max)。这将是第一个研究来评估线粒体的作用,
SC在与慢性疾病(如PH)相关的运动不耐受中的作用,以及
直接靶向SC组装以减轻SkM功能障碍。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Gaurav Choudhary其他文献
Gaurav Choudhary的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Gaurav Choudhary', 18)}}的其他基金
Deep learning for algorithmic detection of pulmonary hypertension using a combined digital stethoscope and single-lead electrocardiogram
使用组合数字听诊器和单导联心电图进行肺动脉高压算法检测的深度学习
- 批准号:
10705310 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Deep learning for algorithmic detection of pulmonary hypertension using a combined digital stethoscope and single-lead electrocardiogram
使用组合数字听诊器和单导联心电图进行肺动脉高压算法检测的深度学习
- 批准号:
10547726 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Role of Endothelial Anoctamin-1 in Pulmonary Arterial Hypertension
内皮 Anoctamin-1 在肺动脉高压中的作用
- 批准号:
10200883 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Role of Endothelial Anoctamin-1 in Pulmonary Arterial Hypertension
内皮 Anoctamin-1 在肺动脉高压中的作用
- 批准号:
10449284 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Role of Endothelial Anoctamin-1 in Pulmonary Arterial Hypertension
内皮 Anoctamin-1 在肺动脉高压中的作用
- 批准号:
9803089 - 财政年份:2019
- 资助金额:
-- - 项目类别:
相似海外基金
Targeting aerobic glycolysis via hexokinase 2 inhibition in Natural Killer T cell lymphomas
通过抑制己糖激酶 2 靶向自然杀伤 T 细胞淋巴瘤中的有氧糖酵解
- 批准号:
23K07830 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (C)
Developing Late Metal Catalytic Systems for Aerobic Partial Oxidation of Alkanes
开发烷烃有氧部分氧化的后金属催化系统
- 批准号:
2247667 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Standard Grant
Concurrent Aerobic Exercise and Cognitive Training to Prevent Alzheimer's in at-risk Older Adults
同时进行有氧运动和认知训练可预防高危老年人的阿尔茨海默病
- 批准号:
10696409 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Precision Medicine in Alzheimer’s Disease: A SMART Trial of Adaptive Exercises and Their Mechanisms of Action Using AT(N) Biomarkers to Optimize Aerobic-Fitness Responses
阿尔茨海默病的精准医学:使用 AT(N) 生物标志物优化有氧健身反应的适应性运动及其作用机制的 SMART 试验
- 批准号:
10581973 - 财政年份:2023
- 资助金额:
-- - 项目类别:
MIND Foods and Aerobic Training in Black Adults with HTN: An ADRD Prevention Pilot RCT (MAT)
MIND 食品和患有 HTN 的黑人成人的有氧训练:ADRD 预防试点随机对照试验 (MAT)
- 批准号:
10585366 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Investigating the physical and chemical controls on aerobic methane oxidation
研究好氧甲烷氧化的物理和化学控制
- 批准号:
2241873 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Standard Grant
Pro-Resolving Inflammatory Mediators in Neurovascular Gains in Aerobic Training; a phase 2, double-blind, randomized placebo-controlled trial (PRIMiNG-AT2)
有氧训练中促进神经血管增益的炎症介质的消除;
- 批准号:
485524 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Operating Grants
Effect of aerobic exercise-induced sleep changes on arterial stiffness associated with postprandial hyperglycemia.
有氧运动引起的睡眠变化对与餐后高血糖相关的动脉僵硬度的影响。
- 批准号:
23K10645 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (C)
Regulators of Photoreceptor Aerobic Glycolysis in Retinal Health and Disease
视网膜健康和疾病中光感受器有氧糖酵解的调节因子
- 批准号:
10717825 - 财政年份:2023
- 资助金额:
-- - 项目类别:
The Effects of Aerobic Exercise on Cardiovascular Health in Postmenopausal Females: A Systematic Review and Meta-Analysis
有氧运动对绝经后女性心血管健康的影响:系统评价和荟萃分析
- 批准号:
480729 - 财政年份:2023
- 资助金额:
-- - 项目类别:














{{item.name}}会员




