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Principal Investigator: Zhen Yan
Organization: VIRGINIA POLYTECHNIC INST AND ST UNIV
Fiscal Year: 2024
Award: $414,641
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
PROJECT SUMMARY/ABSTRACT
Regular exercise promotes physical performance and health, and prevent various types of diseases. These
benefits are largely mediated by responses and adaptations, particularly mitochondrial remodeling, in skeletal
muscle. 5' AMP-activated protein kinase (AMPK) is a bioenergetics sensor that is critical for the maintenance
of metabolic homoeostasis, and AMPK signaling has been linked to mitochondrial remodeling and functional
adaptations under normal and disease conditions. However, the precise mechanism of AMPK signaling in
control of mitochondrial remodeling with subcellular specificity remains obscure. We discovered a physical
association of a novel AMPK complex (α1, β2 and γ1 subunits) with mitochondria (referred to as mitoAMPK) in
and unveiled its activation (T172 phosphorylation) under exercise and ischemic conditions. We have also
obtained preliminary data to show that inhibition of mitoAMPK blocks exercise-induced mitophagy, a key step
in mitochondrial quality control, in skeletal muscle. We now propose a completely novel hypothesis that
mitoAMPK is preferentially activated at energetically stressed mitochondria during exercise, mediating
precision mitophagy of dysfunctional or damaged mitochondria for functional and metabolic
adaptations To test this hypothesis, we propose:
1) Determine if mitoAMPK is preferentially activated at energetically stressed mitochondria in skeletal muscle.
2) Elucidate the role of mitoAMPK in exercise-induced mitophagy.
3) Eetermine the functional role of mitoAMPK in exercise training-induced functional and metabolic
adaptations.
The proposed studies will capitalize on our novel findings of mitoAMPK that reveals completely new
regulatory and functional features of this important signaling molecule in muscle biology and metabolism. The
experimental design and model systems are both conceptually and technically innovative. The findings will
significantly improve the mechanistic understanding of exercise-induced mitophagy and adaptations, with great
potential impact on the future development of therapeutics for treatment and prevention ofchronic diseases,
like type 2 diabetes.
Terms: <(hydroxymethylglutaryl-CoA reductase (NADPH)) kinase><2-photon><21+ years old><5'-AMP-activated protein kinase><AMP-activated kinase><AMP-activated protein kinase><AMPK enzyme><Active Oxygen><Adenine Nucleotides><Adenosine Phosphates><Adult><Adult Human><Adult-Onset Diabetes Mellitus><Autophagocytosis><Bioenergetics><Biologic Models><Biological Models><Biology><Body Tissues><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cas nuclease technology><Cell Communication and Signaling><Cell Signaling><Chronic Disease><Chronic Illness><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Color><Complex><Cultured Cells><Data><Dephosphin><Deterioration><Development><Diabetes Mellitus><Disease><Disorder><Dynamin><E-stim><Electric Stimulation><Ensure><Enzyme Gene><Enzymes><Exercise><Experimental Designs><Experimental Models><FRET><Fluorescence><Fluorescence Resonance Energy Transfer><Foundations><Future><Förster Resonance Energy Transfer><Gene Transfer><HMG CoA reductase (NADPH) kinase><HMG CoA reductase kinase><HMG coenzyme A reductase (NADPH) kinase><Health Benefit><Health Promotion><Heart><Holoenzymes><Human><Image><Insulin Resistance><Intermediary Metabolism><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Ischemia><KO mice><Ketosis-Resistant Diabetes Mellitus><Kidney><Kidney Urinary System><Kinases><Knock-out Mice><Knockout Mice><Laboratories><Link><Maintenance><Maturity-Onset Diabetes Mellitus><Mediating><Membrane Potentials><Metabolic><Metabolic Processes><Metabolism><Mice><Mice Mammals><Mitochondria><Model System><Modern Man><Motor><Murine><Mus><Muscle><Muscle Cell Contraction><Muscle Cells><Muscle Contraction><Muscle Tissue><Muscular Contraction><Myocytes><NIDDM><Nerve><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Null Mouse><Nutrient><Outer Mitochondrial Membrane><Oxidative Phosphorylation><Oxidative Phosphorylation Pathway><Oxidative Stress><Oxygen Radicals><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Physical Performance><Power Plants><Prevention><Pro-Oxidants><Process><Production><Protein Phosphorylation><Proteins><Quality Control><Reactive Oxygen Species><Regulation><Reporter><Resting Potentials><Role><Running><Salutogenesis><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Skeletal Muscle><Slow-Onset Diabetes Mellitus><Specificity><Stable Diabetes Mellitus><Stress><T2 DM><T2D><T2DM><Technology><Testing><Tissues><Transmembrane Potentials><Transphosphorylases><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Visualization><Voluntary Muscle><adult onset diabetes><adulthood><autophagy><biological signal transduction><chronic disorder><developmental><diabetes><effective intervention><electrostimulation><endurance exercise><exercise capacity><exercise training><fighting><frailty><functional adaptation><gain of function><hydroxymethylglutaryl-CoA-reductase kinase><imaging><improved><in vivo><inhibitor><innovate><innovation><innovative><insulin resistant><insulin sensitivity><insulin tolerance><interventional strategy><ketosis resistant diabetes><loss of function><maturity onset diabetes><mitochondrial><muscular><novel><pharmacologic><physical conditioning><physical health><prevent><preventing><promoting health><renal><response><sensor><skeletal><social role><therapeutic agent development><therapeutic development><therapeutically effective><treadmill><two-photon><type 2 DM><type II DM><type two diabetes>