Autocrine Action of Elevated FGF-21 Contributing to Skeletal Muscle Atrophy in Response to Mitochondrial Dysfunction
FGF-21 升高的自分泌作用导致线粒体功能障碍引起的骨骼肌萎缩
基本信息
- 批准号:10296083
- 负责人:
- 金额:$ 45.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-15 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:AblationAcuteAddressAdultAnimalsAtrophicAttenuatedBed restBiochemicalBiologicalBlood CirculationBody CompositionCell physiologyChimeric ProteinsChronicClinicalContusionsDataDiabetes MellitusDiseaseEffectivenessExerciseExhibitsFibroblast Growth FactorGenesGeneticGenetic ModelsGoalsHomeostasisImpairmentInpatientsInterventionLeadLinkMessenger RNAMetabolismMitochondriaModelingMolecularMorbidity - disease rateMusMuscleMuscle DevelopmentMuscle MitochondriaMuscle functionMuscular AtrophyObesityOutcomeOuter Mitochondrial MembraneOxidative StressPathogenesisPathologicPathologyPatientsPerformancePharmacologic SubstancePharmacologyPhysiologicalPhysiologyPredispositionProtein BiosynthesisProteinsPublishingQuality ControlQuality of lifeRecovery of FunctionReportingResearchSignal TransductionSkeletal DevelopmentSkeletal MuscleSpinal Cord ContusionsSpinal cord injuryStressSurgical ModelsTestingTherapeutic Interventionautocrinecomorbidityexercise capacityfibroblast growth factor 21improvedinsightmRNA Expressionmitochondrial dysfunctionmortalitymouse modelmuscle formnew therapeutic targetnoveloverexpressionpreservationpreventreceptorreduced muscle massresponseskeletal circulationskeletal muscle wastingskeletal preservation
项目摘要
PROJECT SUMMARY
Skeletal muscle atrophy and muscle wasting is associated with both acute and chronic pathological conditions
such as traumatic spinal cord injury and inpatient bedrest. Decreases in muscle mass from the atrophy is
associated with power outcomes to other comorbidities, and increased susceptibility to obesity and diabetes.
Current pharmaceutical interventions to increase muscle mass have been limited in their effectiveness. This poor
efficacy is in part due to the limited understanding of the different mechanisms that contribute to decrease muscle
mass. Mitochondrial dysfunction has been proposed as one of the contributors to skeletal muscle atrophy.
However, the precise mechanisms that contribute to impaired mitochondrial functionality and the development
of skeletal muscle atrophy is unknown. Mitochondrial dynamics have emerged as key regulators of both
physiology and pathology in skeletal muscle. We have recently reported that induced adult skeletal muscle
deletion of both mitofusin 1 and 2 have a profound effect on exercise capacity. Furthermore, preliminary analysis
of these animals exhibit signs of decrease muscle mass and the induction of the unfolded protein response
(UPR) and atrophy genes. We also observed elevated levels of FGF21 in skeletal muscle and circulation. These
data suggest that adult skeletal muscle mitochondrial dysfunction and elevated muscle-derived FGF21
contributes to the development of muscle atrophy. Furthermore, utilizing a spinal cord injury (SCI) model, which
develops pathological skeletal muscle atrophy, we observe elevated levels of skeletal muscle Fgf21 mRNA. We
hypothesize that the observed elevated skeletal muscle derived FGF21 in circulation further contributes to the
observed atrophy. Therefore, the overall objective of this proposal is to understand the contribution of
mitochondrial dysfunction in skeletal muscle to the development of skeletal muscle atrophy. Using genetic
models and translatable therapeutic interventions we will attempt to address this very important question. Results
from this proposal have broad implications for our understanding of the molecular changes that contribute to the
development of skeletal muscle atrophy. The specific aims are to: 1.) Establish the requirement of FGF21
signaling for skeletal muscle atrophy in response to muscle mitochondrial dysfunction; 2.) Reveal the
contribution of elevated FGF21 in the development of skeletal muscle atrophy in response to a contusion spinal
cord injury (SCI); 3.) Determine whether pharmacologic inhibition of FGF21 signaling after spinal cord injury
(SCI) prevents skeletal muscle atrophy. This proposal will to provide much needed insights into our
understanding of molecular pathogenesis of skeletal muscle atrophy.
项目总结
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)
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Glenn Cameron Rowe其他文献
Glenn Cameron Rowe的其他文献
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{{ truncateString('Glenn Cameron Rowe', 18)}}的其他基金
Autocrine Action of Elevated FGF-21 Contributing to Skeletal Muscle Atrophy in Response to Mitochondrial Dysfunction
FGF-21 升高的自分泌作用导致线粒体功能障碍引起的骨骼肌萎缩
- 批准号:
10615236 - 财政年份:2021
- 资助金额:
$ 45.9万 - 项目类别:
Autocrine Action of Elevated FGF-21 Contributing to Skeletal Muscle Atrophy in Response to Mitochondrial Dysfunction
FGF-21 升高的自分泌作用导致线粒体功能障碍引起的骨骼肌萎缩
- 批准号:
10469480 - 财政年份:2021
- 资助金额:
$ 45.9万 - 项目类别:
Regulation of Skeletal Muscle Mitochondrial Quality Control Parameters and Systemic Metabolism
骨骼肌线粒体质量控制参数和全身代谢的调节
- 批准号:
9905516 - 财政年份:2019
- 资助金额:
$ 45.9万 - 项目类别:
Regulation of Mitochondria by Exercise and PGC-1 Coactivators in Skeletal Muscle
运动和骨骼肌 PGC-1 共激活剂对线粒体的调节
- 批准号:
9014362 - 财政年份:2015
- 资助金额:
$ 45.9万 - 项目类别:
Regulation of Mitochondria by Exercise and PGC-1 Coactivators in Skeletal Muscle
运动和骨骼肌 PGC-1 共激活剂对线粒体的调节
- 批准号:
9124710 - 财政年份:2015
- 资助金额:
$ 45.9万 - 项目类别:
Regulation of Mitochondria by Exercise and PGC-1 Coactivators in Skeletal Muscle
运动和骨骼肌 PGC-1 共激活剂对线粒体的调节
- 批准号:
8374349 - 财政年份:2012
- 资助金额:
$ 45.9万 - 项目类别:
Regulation of Mitochondria by Exercise and PGC-1 Coactivators in Skeletal Muscle
运动和骨骼肌中 PGC-1 共激活剂对线粒体的调节
- 批准号:
8544780 - 财政年份:2012
- 资助金额:
$ 45.9万 - 项目类别:
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