Uncontrolleddiabetesandinsulinresistanceleadstoenergyimbalance,disruptedproteinturnoverand mitochondrialdysfunction,especiallyinskeletalmuscle.Thesechangescanleadtoacceleratedlossof strengthandmusclewastingwhichincreasestheriskofmorbidityandmortalityinolderindividuals.The signalsthatcontrolmitochondrialmetabolisminmuscleduringdiabetesremainincompletelyunderstood.I havedemonstratedthatinsulinandIGF-1controlmuscleproteinturnovertomaintainmusclemass,andthat thiscontrolisdependentonFoxOtranscriptionfactors.Furthermore,preliminarystudiesshowthatinsulin- deficientdiabetesleadstomusclewastingthroughcellularautophagy,or?selfeating?,thatcanbeprevented bydeletionofFoxOsinmuscle.ThegoalofthisproposalistoinvestigatewhetherFoxOproteinscontrol musclemitochondrialmetabolismandmitochondrial-specificautophagy,or?mitophagy?inthecontextof diabetes.However,aquantitativemethodtomeasuremitophagyinmuscleisnotcurrentlyavailable.To accomplishthegoalsofthisprojectIwill(a)measuremusclemitochondrialrespirationinmicewithmuscle- specificdeletionofFoxOisoforms(FoxOTKO)thatarerendereddiabeticusingstreptozotocinandcorrelate thiswithmeasuresofmitophagyincellslackingFoxOs,and(b)developaquantitativemethodtomeasure mitophagyinmuscletissueusingproximityligationassaycoupledtorollingcircleamplification(PLA/RCA). Mylong-termgoalsaretounderstandtheimpactofdiabetesandinsulinresistanceonproteinturnovertogain insightsintothemetabolicandmitochondrialchangesthatcanimpactcomplicationsofthisdisease.

Public Health Relevance

Uncontrolleddiabetesinolderindividualscandecreasemusclesizeandstrength,andis associatedwithinefficientenergyproductioninthecellularpowerhouses(akamitochondria). OurpreviousworkhasshownthatinsulincontrolsmusclesizebyturningoffFoxOproteinsto controlcellularautophagy,or?self-eating?.ThegoalofthisprojectistoseeifFoxOsalso controltheself-eatingofmitochondria,or?mitophagy?,whichwillhelpusbetterunderstandthe connectionsbetweendiabetesandmuscleweaknessthatmaycontributetodisability.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
1R03DK112003-01
Application #
9227807
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK-B)
Program Officer
Spain, Lisa M
Project Start
2017-03-05
Project End
2019-02-28
Budget Start
2017-03-05
Budget End
2018-02-28
Support Year
1
Fiscal Year
2017
Total Cost
$76,250
Indirect Cost
$26,250
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52246