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Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis
Brian T. O’Neill, … , K. Sreekumaran Nair, C. Ronald Kahn
Brian T. O’Neill, … , K. Sreekumaran Nair, C. Ronald Kahn
Published August 15, 2016
Citation Information: J Clin Invest. 2016;126(9):3433-3446. https://doi.org/10.1172/JCI86522.
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Research Article Endocrinology

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

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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.

Authors

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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Figure 4

FoxO transcription factors display nuclear accumulation in fed MIGIRKO mice with increases in transcription of FoxO target genes.

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FoxO transcription factors display nuclear accumulation in fed MIGIRKO m...
(A) Western blot of FoxO1, FoxO3, and FoxO4 in nuclear and cytoplasmic fractions of muscle from fed or overnight-fasted MIGIRKO and control mice (n = 2 per group). PARP and GAPDH are used as nuclear and cytoplasmic markers, respectively. (B and C) qPCR of FoxO target genes (B) and autophagy intermediates (C) in TA from MIGIRKO and control mice either randomly fed or fasted overnight. (D) qPCR of proteasome subunits and E3-ubiquitin ligases in TA from MIGIRKO and control mice either randomly fed or fasted overnight (n = 4–8 per group). (*P < 0.05, **P < 0.01 control vs. MIGIRKO; †P < 0.05, ††P < 0.01 fed vs. fasted, 2-way ANOVA.)

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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