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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 7

Deletion of FoxO1/3/4 in MIGIRKO mice reverses muscle atrophy and muscle dysfunction, but deletion of a single FoxO isoform does not.

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Deletion of FoxO1/3/4 in MIGIRKO mice reverses muscle atrophy and muscle...
(A) Muscle weights from control, MIGIRKO, M-FoxO TKO, and M-QKO mice (n = 6–9). (B) Grip strength in control, MIGIRKO, M-FoxO TKO, and M-QKO mice (n = 12 pooled controls and 5–9 KO mice; MIGIRKO data are the same as in Figure 1I). (C and D) Myofiber cross-sectional (CS) area (C) and myofiber distribution (D) of laminin-stained TA sections from control, MIGIRKO, M-FoxO TKO, and M-QKO mice (n = 4). (E) Survival curves for control, MIGIRKO, and M-QKO female mice (n = 6–7). (F) Western blot of IR, IGF1R, and FoxO isoforms in TA from control, MIGIRKO, MIGIRKO plus FoxO1 knockout (MIG-FoxO1–/–), MIGIRKO plus FoxO3 knockout (MIG-FoxO3–/–), MIGIRKO plus FoxO4 knockout (MIG-FoxO4–/–), and M-QKO mice. (G) Dissected muscle weights normalized to littermate lox controls from MIGIRKO, MIG-FoxO1–/–, MIG-FoxO3–/–, MIG-FoxO4–/–, and M-QKO mice (n = 4–10 per group). (**P < 0.01 vs. control; †P < 0.05, ††P < 0.01 vs. MIGIRKO, ANOVA.) Blots are from parallel samples run on separate gels.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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