Journal article
FoxO Transcription Factors Are Critical Regulators of Diabetes-Related Muscle Atrophy
Diabetes (New York, N.Y.), Vol.68(3), pp.556-570
03/01/2019
DOI: 10.2337/db18-0416
PMCID: PMC6385751
PMID: 30523026
Abstract
Insulin deficiency and uncontrolled diabetes lead to a catabolic state with decreased muscle strength, contributing to disease-related morbidity. FoxO transcription factors are suppressed by insulin and thus are key mediators of insulin action. To study their role in diabetic muscle wasting, we created mice with muscle-specific triple knockout of Fox01/3/4 and induced diabetes in these M-FoxO-TKO mice with streptozotocin (STZ). Muscle mass and myofiber area were decreased 20-30% in STZ-Diabetes mice due to increased ubiquitin-proteasome degradation and autophagy alterations, characterized by increased LC3-containing vesicles, and elevated levels of phosphorylated ULK1 and LC3-II. Both the muscle loss and markers of increased degradation/autophagy were completely prevented in STZ FoxO-TKO mice. Transcriptomic analyses revealed FoxO-dependent increases in ubiquitin-mediated proteolysis pathways in STZ-Diabetes, including regulation of Fbxo32 (Atrogin1), Trim63 (MuRF1), Bnip3L, and Gabarapl. These same genes were increased 1.4- to 3.3-fold in muscle from humans with type 1 diabetes after shortterm insulin deprivation. Thus, FoxO-regulated genes play a rate-limiting role in increased protein degradation and muscle atrophy in insulin-deficient diabetes.
Details
- Title: Subtitle
- FoxO Transcription Factors Are Critical Regulators of Diabetes-Related Muscle Atrophy
- Creators
- Brian T. O'Neill - Univ Iowa, Roy J & Lucille A Carver Coll Med, Fraternal Order Eagles Diabet Res Ctr, Iowa City, IA USAGourav Bhardwaj - University of IowaChristie M. Penniman - University of IowaMegan T. Krumpoch - Joslin Diabetes CenterPablo A. Suarez Beltran - Roy J. and Lucille A. Carver College of MedicineKatherine Klaus - Mayo ClinicKennedy Poro - Roy J. and Lucille A. Carver College of MedicineMengyao Li - Joslin Diabetes CenterHui Pan - Joslin Diabetes CenterJonathan M. Dreyfuss - Joslin Diabetes CenterK. Sreekumaran Nair - Mayo ClinicC. Ronald Kahn - Joslin Diabetes Center
- Resource Type
- Journal article
- Publication Details
- Diabetes (New York, N.Y.), Vol.68(3), pp.556-570
- DOI
- 10.2337/db18-0416
- PMID
- 30523026
- PMCID
- PMC6385751
- NLM abbreviation
- Diabetes
- ISSN
- 0012-1797
- eISSN
- 1939-327X
- Publisher
- Amer Diabetes Assoc
- Number of pages
- 15
- Grant note
- UL1-TR-000135 / Mayo Clinic Clinical and Translational Science Awards grant from National Center for Advancing Translational Sciences of the NIH R01-DK-031036; R01-DK-033201; R01-DK-41973; U24-DK-100469 / National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) K08-DK-100543 / K08 training award from the NIDDK P30-DK-36836 / Joslin Diabetes and Endocrinology Research Center R01DK031036 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) U24-DK-100469 / Mayo Clinic Metabolomics Resource Core grant from the NIDDK R03-DK-112003 / R03 award from the NIDDK
- Language
- English
- Date published
- 03/01/2019
- Academic Unit
- Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984359916002771
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