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Principal Investigator: Lie Gao
Organization: UNIVERSITY OF NEBRASKA MEDICAL CENTER
Fiscal Year: 2024
Award: $508,114
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
The goal of this study is to elucidate novel mechanisms underlying exercise training (ExT)-induced sympatho-
inhibition in chronic heart failure (CHF) (Aim 1) and cardioprotection following acute coronary
ischemia/reperfusion (I/R) (Aim 2), based on an innovative concept of inter-organ transfer of antioxidant
enzymes. It is well established that exercise generates muscle-derived reactive oxygen species (ROS) which
activates nuclear factor (erythroid-derived 2)-like 2 (Nrf2), resulting in upregulation of a panel of antioxidant
enzymes in skeletal muscle per se. We hypothesize that these antioxidants can be transported from skeletal
muscle to remote tissues through circulating extracellular vesicles (EVs), providing recipient cells with a
second and enhanced line of antioxidant defense. In the rostral ventrolateral medulla (RVLM) of mice with
CHF, these antioxidants restore redox homeostasis of pre-sympathetic neurons, contributing to ExT-sympatho-
inhibition. Furthermore, in the heart of mice subjected to coronary I/R, these antioxidants reduce free radical
damage and salvage ischemic myocardium, thus playing a critical role in ExT-cardioprotection. To address
these hypotheses, we developed three skeletal muscle-specific transgenic mouse lines. The MS-mG line is a
reporter model, which allows us to track, capture, and analyze EVs released specifically from skeletal muscle.
This model will be used to assay cargo proteins of skeletal muscle-derived EVs and their distribution in brain
and heart following ExT. The iMS-Nrf2flox/flox and iMS-Keap1flox/flox lines will enable us to delete skeletal muscle
Nrf2 (i.e. Nrf2 deficiency) and Keap1 (i.e. Nrf2 overexpression), respectively. These two models will be used to
demonstrate a causal relationship between the Nrf2/antioxidant system and ExT-sympatho-inhibition in Aim 1
and ExT-cardioprotection in Aim 2. Interdisciplinary methods of EV biology, proteomics, bioinformatics,
electrophysiology, and cardiovascular physiology will be utilized to characterize skeletal muscle-derived EVs
following ExT, determine the effects of ExT-EVs on central neuron discharge and peripheral sympathetic nerve
activity, and explore the mechanisms underpinning cardioprotection of ExT-EVs against coronary I/R injury.
Upon completion of this project, we expect to provide novel mechanistic insights on ExT-cardiovascular
protection, paving a new avenue to translate the beneficial effects of regular physical activity into clinical
practice to prevent and treat acute and chronic ischemic heart diseases.
Terms: <Active Oxygen><Acute><Address><Antioxidants><Assay><Autoregulation><Basal Transcription Factor><Basal transcription factor genes><Bio-Informatics><Bioassay><Bioinformatics><Biological Assay><Biology><Blood flow><Body Tissues><Brain><Brain Nervous System><Brain Stem><Brainstem><Cardiac><Cardiac Failure Congestive><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular Physiology><Cardiovascular system><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell membrane><Cell to Cell Communication and Signaling><Cell-Cell Signaling><Cells><Chronic><Common Rat Strains><Communication><Congestive Heart Failure><Contracting Opportunities><Contracts><Cytoplasmic Membrane><Cytosol><Defense Mechanisms><Disease><Disorder><Distant><Dysfunction><E-stim><ECG><EKG><Echocardiogram><Echocardiography><Electric Stimulation><Electrocardiogram><Electrocardiography><Electrophysiology><Electrophysiology (science)><Encephalon><Erythroid><Exercise><Femur><Free Radicals><Functional disorder><General Transcription Factor Gene><General Transcription Factors><Goals><Health><Heart><Heart Decompensation><Heart Vascular><Hindlimb><Homeostasis><Human><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Investigation><Ischemia><Ischemia-Reperfusion Injury><Ischemic Heart><Ischemic Heart Disease><Ischemic myocardium><Laboratories><Left><Lipid Bilayers><LoxP-flanked allele><Maintenance><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measurement><Mediating><Methods><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Murine><Mus><Muscle><Muscle Cell Contraction><Muscle Contraction><Muscle Tissue><Muscular Contraction><Myocardial><Myocardial Ischemia><Myocardial Ischemic Reperfusion Injury><Myocardial Reperfusion Injury><Myocardium><Nerve><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Neurophysiology / Electrophysiology><Nuclear><Organ><Oxidation-Reduction><Oxidative Stress><Oxygen Radicals><Parents><Pathway interactions><Performance><Peripheral><Physical activity><Physiological Homeostasis><Physiopathology><Plasma Membrane><Play><Preparation><Pro-Oxidants><Prognosis><Proteins><Proteomics><Rat><Rats Mammals><Rattus><Reactive Oxygen Species><Redox><Regulation><Reperfusion Damage><Reperfusion Injury><Reperfusion Therapy><Reporter><Resistance><Rest><Role><Sedentary behavior><Sedentary life-style><Signal Transduction><Signal Transduction Systems><Signaling><Skeletal Muscle><Stress><System><Testing><Tissues><Transcription Factor Proto-Oncogene><Transcription factor genes><Transgenic Mice><Translating><Transthoracic Echocardiography><Travel><Up-Regulation><Upregulation><Ventricular><Voluntary Muscle><anti-oxidant enzyme><antioxidant enzyme><biological signal transduction><cardiac function><cardiac ischemia><cardiac muscle><cardioprotectant><cardioprotection><cardioprotective><cardiovascular disorder><cardiovascular function><cardiovascular risk><cardiovascular risk factor><chronic heart failure><circulatory system><clinical practice><coronary ischemia><electrophysiological><electrostimulation><exercise training><extracellular vesicles><floxed><floxed allele><function of the heart><heart function><heart infarct sizing><heart infarction sizing><heart ischemia><heart muscle><heart sonography><hemodynamics><improved><indexing><innovate><innovation><innovative><insight><intercellular communication><interventional strategy><lipid bilayer membrane><mimetics><muscular><myocardial infarct sizing><myocardial infarction sizing><myocardial ischemia/hypoxia><myocardium ischemia><neuronal><novel><overexpress><overexpression><oxidation reduction reaction><parent><particle><pathophysiology><pathway><pharmacologic><plasmalemma><preparations><prevent><preventing><protective factors><psychological defense mechanism><release factor><reperfusion><resistant><sedentary lifestyle><social role><transcription factor><vesicle release><vesicular release>