title: Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis.
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.forename: Brian T
authors.initials: BT
authors.lastname: O'Neill
authors.forename: Kevin Y
authors.initials: KY
authors.lastname: Lee
authors.forename: Katherine
authors.initials: K
authors.lastname: Klaus
authors.forename: Samir
authors.initials: S
authors.lastname: Softic
authors.forename: Megan T
authors.initials: MT
authors.lastname: Krumpoch
authors.forename: Joachim
authors.initials: J
authors.lastname: Fentz
authors.forename: Kristin I
authors.initials: KI
authors.lastname: Stanford
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Robinson
authors.forename: Weikang
authors.initials: W
authors.lastname: Cai
authors.forename: Andre
authors.initials: A
authors.lastname: Kleinridders
authors.forename: Renata O
authors.initials: RO
authors.lastname: Pereira
authors.forename: Michael F
authors.initials: MF
authors.lastname: Hirshman
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
authors.forename: Domenico
authors.initials: D
authors.lastname: Accili
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Goodyear
authors.forename: K Sreekumaran
authors.initials: KS
authors.lastname: Nair
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
mesh_terms: D000818:Animals; D001343:Autophagy; D002454:Cell Differentiation; D005260:Female; D000071161:Forkhead Box Protein O1 / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D007328:Insulin / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009133:Muscular Atrophy / Q000378:metabolism; D032446:Myoblasts / Q000378:metabolism; D010100:Oxygen / Q000737:chemistry; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000071161:Forkhead Box Protein O1; C467200:Foxo1 protein, mouse; D007328:Insulin; D009124:Muscle Proteins; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D046988:Proteasome Endopeptidase Complex; D010100:Oxygen