Abstract
299-OR: Loss of Insulin and IGF1 Receptors in Muscle Impairs Complex-I Dependent Mitochondrial Bioenergetics and Supercomplex Formation via Foxo Transcription Factors
Diabetes (New York, N.Y.), Vol.69(Supplement_1)
06/01/2020
DOI: 10.2337/db20-299-OR
Abstract
Diabetes is associated with decreased muscle strength and mitochondrial metabolism which can lead to disability. Recently, we reported that insulin receptor (IR) and IGF-1 receptor (IGF1R) prevent muscle atrophy via suppression of FoxOs, but how FoxOs interact with mitochondrial function remains unclear. To test whether IR/IGF1R suppression of FoxOs coordinates muscle strength with mitochondrial function, we measured mitochondrial bioenergetics and RNA-Seq in mice lacking IR, IGF1R, and/or FoxO1/3/4 in muscle. Perinatal muscle-specific deletion of IR (MIRKO) showed a mild 20% decrease in pyruvate-driven respiratory capacity in soleus permeabilized fibers, whereas succinate/Rotenone respiration was not different. Deletion of both IR/IGF1R (MIGIRKO) showed a marked 60% decrease in pyruvate respiration and ATP production in soleus fibers. These mitochondrial abnormalities were reversed in muscle-specific IR/IGF1R and FoxO1/3/4 quintuple knockout (QKO), suggesting FoxO activation mediates the mitochondrial decline. FoxOs are known inducers of autophagy, but mitophagy quantification using MitoTIMER or mitoKeima biosensors was not altered in Day 21 Tamoxifen-inducible IR/IGF1R KO in adult muscle (IND-IGIRKO) or by acute in-vitro deletion of IR/IGF1R primary myotubes. Complex-I activity was decreased 50-70% in MIGIRKO and Day 21 IND-IGIRKO muscle, but other complex activities were unchanged. Furthermore, 14 complex-I subunits were decreased in MIGIRKO by RNA-Seq, and 13 of these were reversed in QKO. IND-IGIRKO also showed a decrease in pyruvate respiration, ATP production, complex-I activity, and complex-I/supercomplex content by blue-native gels 21 days after tamoxifen. Thus, loss of IR or both IR/IGF1R in muscle decreases complex-I driven mitochondrial respiration and supercomplex assemblies, at least in part by FoxO-mediated downregulation of mitochondrial genes. Disclosure G. Bhardwaj: None. C.M. Penniman: None. P.A. Suarez Beltran: None. J. Jena: None. C.M. Foster: None. K. Poro: None. T. Junck: None. A. Hinton: None. R. Souvenir: None. J. Fuqua: None. P.E. Morales: None. R. Bravo-Sagua: None. V.A. Lira: None. E.D. Abel: None. B.T. ONeill: None.
Details
- Title: Subtitle
- 299-OR: Loss of Insulin and IGF1 Receptors in Muscle Impairs Complex-I Dependent Mitochondrial Bioenergetics and Supercomplex Formation via Foxo Transcription Factors
- Creators
- GOURAV Bhardwaj - Iowa City, IA, Santiago, ChileCHRISTIE M. Penniman - Iowa City, IA, Santiago, ChilePABLO A. SUAREZ Beltran - Iowa City, IA, Santiago, ChileJAYASHREE Jena - Iowa City, IA, Santiago, ChileCOLLIN M. Foster - Iowa City, IA, Santiago, ChileKENNEDY Poro - Iowa City, IA, Santiago, ChileTAYLOR Junck - Iowa City, IA, Santiago, ChileANTENTOR Hinton - Iowa City, IA, Santiago, ChileRHONDA Souvenir - Iowa City, IA, Santiago, ChileJORDAN Fuqua - Iowa City, IA, Santiago, ChilePABLO E. Morales - Iowa City, IA, Santiago, ChileROBERTO BRAVO-SAGUA - Iowa City, IA, Santiago, ChileVITOR A. Lira - Iowa City, IA, Santiago, ChileEVAN D. Abel - Iowa City, IA, Santiago, ChileBRIAN T. Oneill - Iowa City, IA, Santiago, Chile
- Resource Type
- Abstract
- Publication Details
- Diabetes (New York, N.Y.), Vol.69(Supplement_1)
- DOI
- 10.2337/db20-299-OR
- ISSN
- 0012-1797
- eISSN
- 1939-327X
- Language
- English
- Date published
- 06/01/2020
- Academic Unit
- Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Health and Human Physiology; Internal Medicine
- Record Identifier
- 9984267156402771
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