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- Title
FoxO Transcription Factors Are Critical Regulators of Diabetes-Related Muscle Atrophy.
- Authors
O'Neill, Brian T.; Bhardwaj, Gourav; Penniman, Christie M.; Krumpoch, Megan T.; Beltran, Pablo A. Suarez; Klaus, Katherine; Poro, Kennedy; Mengyao Li; Hui Pan; Dreyfuss, Jonathan M.; Nair, K. Sreekumaran; Kahn, C. Ronald; Suarez Beltran, Pablo A; Li, Mengyao; Pan, Hui
- 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 FoxO1/3/4 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 short-term insulin deprivation. Thus, FoxO-regulated genes play a rate-limiting role in increased protein degradation and muscle atrophy in insulin-deficient diabetes.
- Subjects
TRANSCRIPTION factors; PROTEOLYSIS; TYPE 1 diabetes; MUSCLE strength; MUSCLES; ATROPHY
- Publication
Diabetes, 2019, Vol 68, Issue 3, p556
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db18-0416