TitleInsulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis.
Publication TypeJournal Article
Year of Publication2016
AuthorsO'Neill, BT, Lee, KY, Klaus, K, Softic, S, Krumpoch, MT, Fentz, J, Stanford, KI, Robinson, MM, Cai, W, Kleinridders, A, Pereira, RO, Hirshman, MF, E Abel, D, Accili, D, Goodyear, LJ, K Nair, S, C Kahn, R
JournalJ Clin Invest
Date Published2016 Sep 01

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.

Alternate JournalJ. Clin. Invest.
PubMed ID27525440
PubMed Central IDPMC5004956
Grant ListR01 AR042238 / AR / NIAMS NIH HHS / United States
R01 DK041973 / DK / NIDDK NIH HHS / United States
K08 DK100543 / DK / NIDDK NIH HHS / United States
U24 DK100469 / DK / NIDDK NIH HHS / United States
P30 DK036836 / DK / NIDDK NIH HHS / United States
K01 DK105109 / DK / NIDDK NIH HHS / United States
UL1 TR000135 / TR / NCATS NIH HHS / United States
R01 DK031036 / DK / NIDDK NIH HHS / United States