FOXO transcription factors are critical regulators of diabetes-related muscle atrophy

Brian T. O’Neill, Gourav Bhardwaj, Christie M. Penniman, Megan T. Krumpoch, Pablo A. Suarez Beltran, Katherine Klaus, Kennedy Poro, Mengyao Li, Hui Pan, Jonathan M. Dreyfuss, K Sreekumaran Nair, C. Ronald Kahn

Research output: Contribution to journalArticle

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)556-570
Number of pages15
JournalDiabetes
Volume68
Issue number3
DOIs
StatePublished - Mar 1 2019
Externally publishedYes

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ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

O’Neill, B. T., Bhardwaj, G., Penniman, C. M., Krumpoch, M. T., Suarez Beltran, P. A., Klaus, K., Poro, K., Li, M., Pan, H., Dreyfuss, J. M., Nair, K. S., & Ronald Kahn, C. (2019). FOXO transcription factors are critical regulators of diabetes-related muscle atrophy. Diabetes, 68(3), 556-570. https://doi.org/10.2337/db18-0416