Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis

Brian T. O'Neill, Kevin Y. Lee, Katherine Klaus, Samir Softic, Megan T. Krumpoch, Joachim Fentz, Kristin I. Stanford, Matthew M. Robinson, Weikang Cai, Andre Kleinridders, Renata O. Pereira, Michael F. Hirshman, E. Dale Abel, Domenico Accili, Laurie J. Goodyear, K Sreekumaran Nair, C. Ronald Kahn

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Abstract

Diabetes strongly impacts protein metabolism, particularly in skeletal muscle. Insulin and IGF-1 enhance muscle protein synthesis through their receptors, but the relative roles of each in muscle proteostasis have not been fully elucidated. Using mice with muscle-specific deletion of the insulin receptor (M-IR-/- mice), the IGF-1 receptor (M-IGF1R-/- mice), or both (MIGIRKO mice), we assessed the relative contributions of IR and IGF1R signaling to muscle proteostasis. In differentiated muscle, IR expression predominated over IGF1R expression, and correspondingly, M-IR-/- mice displayed a moderate reduction in muscle mass whereas M-IGF1R-/- mice did not. However, these receptors serve complementary roles, such that double-knockout MIGIRKO mice displayed a marked reduction in muscle mass that was linked to increases in proteasomal and autophagy-lysosomal degradation, accompanied by a high-protein-turnover state. Combined muscle-specific deletion of FoxO1, FoxO3, and FoxO4 in MIGIRKO mice reversed increased autophagy and completely rescued muscle mass without changing proteasomal activity. These data indicate that signaling via IR is more important than IGF1R in controlling proteostasis in differentiated muscle. Nonetheless, the overlap of IR and IGF1R signaling is critical to the regulation of muscle protein turnover, and this regulation depends on suppression of FoxO-regulated, autophagy-mediated protein degradation.

Original languageEnglish (US)
Pages (from-to)3433-3446
Number of pages14
JournalJournal of Clinical Investigation
Volume126
Issue number9
DOIs
StatePublished - Sep 1 2016

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IGF Type 1 Receptor
Insulin
Muscles
Autophagy
Muscle Proteins
Insulin Receptor
Insulin-Like Growth Factor I
Knockout Mice
Proteolysis
Skeletal Muscle
Proteins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

O'Neill, B. T., Lee, K. Y., Klaus, K., Softic, S., Krumpoch, M. T., Fentz, J., ... Kahn, C. R. (2016). Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis. Journal of Clinical Investigation, 126(9), 3433-3446. https://doi.org/10.1172/JCI86522

Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis. / O'Neill, Brian T.; Lee, Kevin Y.; Klaus, Katherine; Softic, Samir; Krumpoch, Megan T.; Fentz, Joachim; Stanford, Kristin I.; Robinson, Matthew M.; Cai, Weikang; Kleinridders, Andre; Pereira, Renata O.; Hirshman, Michael F.; Abel, E. Dale; Accili, Domenico; Goodyear, Laurie J.; Nair, K Sreekumaran; Kahn, C. Ronald.

In: Journal of Clinical Investigation, Vol. 126, No. 9, 01.09.2016, p. 3433-3446.

Research output: Contribution to journalArticle

O'Neill, BT, Lee, KY, Klaus, K, Softic, S, Krumpoch, MT, Fentz, J, Stanford, KI, Robinson, MM, Cai, W, Kleinridders, A, Pereira, RO, Hirshman, MF, Abel, ED, Accili, D, Goodyear, LJ, Nair, KS & Kahn, CR 2016, 'Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis', Journal of Clinical Investigation, vol. 126, no. 9, pp. 3433-3446. https://doi.org/10.1172/JCI86522
O'Neill BT, Lee KY, Klaus K, Softic S, Krumpoch MT, Fentz J et al. Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis. Journal of Clinical Investigation. 2016 Sep 1;126(9):3433-3446. https://doi.org/10.1172/JCI86522
O'Neill, Brian T. ; Lee, Kevin Y. ; Klaus, Katherine ; Softic, Samir ; Krumpoch, Megan T. ; Fentz, Joachim ; Stanford, Kristin I. ; Robinson, Matthew M. ; Cai, Weikang ; Kleinridders, Andre ; Pereira, Renata O. ; Hirshman, Michael F. ; Abel, E. Dale ; Accili, Domenico ; Goodyear, Laurie J. ; Nair, K Sreekumaran ; Kahn, C. Ronald. / Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis. In: Journal of Clinical Investigation. 2016 ; Vol. 126, No. 9. pp. 3433-3446.
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