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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 1

IR predominates over IGF1R in differentiated muscle, and combined deletion of IR and Igf1r in muscle dramatically decreases muscle fiber size and muscle function.

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IR predominates over IGF1R in differentiated muscle, and combined deleti...
(A) Copy number of insulin receptor (IR) and IGF-1 receptor (Igf1r) mRNA was measured by qPCR in undifferentiated (day –2) primary mouse myoblasts, differentiated myotubes (day +7) (n = 3 experiments), and tibialis anterior (TA) muscle from 8-week-old male mice (n = 7). Copy number was quantitated using a standard curve obtained by serial dilution of IR and IGF1R cDNA plasmids (##P < 0.01 vs. insulin receptor in same group; ††P < 0.01 vs. IGF-1 receptor in each other group). (B) Muscle weights from 8-week-old knockout and control mice (n = 21 controls and 5–10 knockouts). (C) Laminin staining of TA muscle cross sections (scale bar: 200 μm). (D and E) Muscle fiber cross-sectional area (D) and myofiber size distribution (E) of TA from C (n = 5–11). (F) Distance run in kilometers (km) by females during a 30-day voluntary wheel cage running experiment (n = 16 controls and 4–8 knockouts). (G and H) Time to exhaustion (G) and maximum distance run (H) during an acute treadmill test of MIGIRKO and control mice (n = 6). (I) Forelimb grip strength in control, M-IR–/–, M-IGF1R–/–, and MIGIRKO mice (n = 16 controls and 4–8 knockouts). (*P < 0.05, **P < 0.01 vs. control, t test for 2 groups, ANOVA for 3 or more.)

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