Journal article
Insulin and IGF-1 receptors regulate complex I-dependent mitochondrial bioenergetics and supercomplexes via FoxOs in muscle
The Journal of clinical investigation, Vol.131(18), e146415
09/15/2021
DOI: 10.1172/JCI146415
PMCID: PMC8439595
PMID: 34343133
Abstract
Decreased skeletal muscle strength and mitochondrial dysfunction are characteristic of diabetes. The actions of insulin and IGF-1 through the insulin receptor (IR) and IGF-1 receptor (IGF1R) maintain muscle mass via suppression of forkhead box O (FoxO) transcription factors, but whether FoxO activation coordinates atrophy in concert with mitochondrial dysfunction is unknown. We show that mitochondrial respiration and complex I activity were decreased in streptozotocin (STZ) diabetic muscle, but these defects were reversed in muscle-specific FoxO1, -3, and -4 triple-KO (M-FoxO TKO) mice rendered diabetic with STZ. In the absence of systemic glucose or lipid abnormalities, muscle-specific IR KO (M-IR-/-) or combined IR/IGF1R KO (MIGIRKO) impaired mitochondrial respiration, decreased ATP production, and increased ROS. These mitochondrial abnormalities were not present in muscle-specific IR, IGF1R, and FoxO1, -3, and -4 quintuple-KO mice (M-QKO). Acute tamoxifen-inducible deletion of IR and IGF1R also decreased muscle pyruvate respiration, complex I activity, and supercomplex assembly. Although autophagy was increased when IR and IGF1R were deleted in muscle, mitophagy was not increased. Mechanistically, RNA-Seq revealed that complex I core subunits were decreased in STZ-diabetic and MIGIRKO muscle, and these changes were not present with FoxO KO in STZ-FoxO TKO and M-QKO mice. Thus, insulin-deficient diabetes or loss of insulin/IGF-1 action in muscle decreases complex I-driven mitochondrial respiration and supercomplex assembly in part by FoxO-mediated repression of complex I subunit expression.
Details
- Title: Subtitle
- Insulin and IGF-1 receptors regulate complex I-dependent mitochondrial bioenergetics and supercomplexes via FoxOs in muscle
- Creators
- Gourav Bhardwaj - Roy J. and Lucille A. Carver College of MedicineChristie M Penniman - Roy J. and Lucille A. Carver College of MedicineJayashree Jena - University of IowaPablo A Suarez Beltran - Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USACollin Foster - Roy J. and Lucille A. Carver College of MedicineKennedy Poro - Roy J. and Lucille A. Carver College of MedicineTaylor L Junck - Roy J. and Lucille A. Carver College of MedicineAntentor O Hinton Jr - Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USARhonda Souvenir - University of IowaJordan D Fuqua - University of IowaPablo E Morales - University of ChileRoberto Bravo-Sagua - University of ChileWilliam I Sivitz - Roy J. and Lucille A. Carver College of MedicineVitor A Lira - University of IowaE Dale Abel - University of IowaBrian T O'Neill - Veterans Affairs Health Care System, Iowa City, Iowa, USA
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.131(18), e146415
- DOI
- 10.1172/JCI146415
- PMID
- 34343133
- PMCID
- PMC8439595
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Grant note
- T32 DK091317 / NIDDK NIH HHS T32 HL007344 / NHLBI NIH HHS R01 HL127764 / NHLBI NIH HHS I01 BX000285 / BLRD VA R01 HL112413 / NHLBI NIH HHS I01 BX004468 / BLRD VA P30 DK054759 / NIDDK NIH HHS
- Language
- English
- Date published
- 09/15/2021
- Academic Unit
- Fraternal Order of Eagles Diabetes Research Center; Dental Research; Endocrinology and Metabolism; Health and Human Physiology; Internal Medicine
- Record Identifier
- 9984259639202771
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