TY - JOUR
T1 - Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis
AU - O'Neill, Brian T.
AU - Lee, Kevin Y.
AU - Klaus, Katherine
AU - Softic, Samir
AU - Krumpoch, Megan T.
AU - Fentz, Joachim
AU - Stanford, Kristin I.
AU - Robinson, Matthew M.
AU - Cai, Weikang
AU - Kleinridders, Andre
AU - Pereira, Renata O.
AU - Hirshman, Michael F.
AU - Abel, E. Dale
AU - Accili, Domenico
AU - Goodyear, Laurie J.
AU - Nair, K. Sreekumaran
AU - Kahn, C. Ronald
N1 - Funding Information:
This work was supported by NIH grants R01 DK031036 (to CRK), R01 AR42238 (to LJG), and R01 DK41973 and U24 DK100469 (to KSN). BTO was funded by a K08 training award from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the NIH (K08 DK100543), Mayo Clinic Metabolomics Resource Core grant U24 DK100469 from the NIDDK, which originates from the NIH Director's Common Fund, and Mayo Clinic Clinical and Translational Science Awards grant UL1 TR000135 from the National Center for Advancing Translational Sciences of the NIH. KIS was funded by a K01 award from the NIDDK of the NIH (K01 DK105109). AK was supported by a German Research Foundation (DFG) fellowship Kl2399-1/1 grant. The Joslin Diabetes Research Center core facility was used for part of this work (P30 DK36836)
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI86522
DO - 10.1172/JCI86522
M3 - Article
C2 - 27525440
AN - SCOPUS:84987792901
SN - 0021-9738
VL - 126
SP - 3433
EP - 3446
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 9
ER -