Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis
| Autor: | Megan T. Krumpoch, C. Ronald Kahn, Matthew M. Robinson, Michael F. Hirshman, Kevin Y. Lee, K. Sreekumaran Nair, Domenico Accili, Kristin I. Stanford, André Kleinridders, E. Dale Abel, Laurie J. Goodyear, Joachim Fentz, Katherine A. Klaus, Renata O. Pereira, Weikang Cai, Samir Softic, Brian T. O’Neill |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Proteasome Endopeptidase Complex Muscle Proteins FOXO1 Protein degradation Receptor IGF Type 1 Myoblasts Mice 03 medical and health sciences Autophagy medicine Animals Insulin Phosphorylation Muscle Skeletal Receptor Insulin-like growth factor 1 receptor Mice Knockout biology Forkhead Box Protein O1 Chemistry Skeletal muscle Cell Differentiation General Medicine Receptor Insulin Cell biology Oxygen body regions Muscular Atrophy Insulin receptor 030104 developmental biology medicine.anatomical_structure Proteostasis Gene Expression Regulation biology.protein Female Signal transduction Lysosomes Gene Deletion Research Article Signal Transduction |
| Zdroj: | The journal of clinical investigation, 126(9): 3433-3446 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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