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