IGF-I stimulates protein synthesis in skeletal muscle through multiple signaling pathways during sepsis

Abstract

Chronic septic abscess formation causes an inhibition of protein synthesis in gastrocnemius not observed in rats with a sterile abscess. Inhibition is associated with an impaired mRNA translation initiation that can be ameliorated by elevating IGF-I but not insulin. The present study investigated the ability of IGF-I signaling to stimulate protein synthesis in gastrocnemius by accelerating mRNA translation initiation. Experiments were performed in perfused hindlimb preparations from rats 5 days after induction of a septic abscess. Protein synthesis in gastrocnemius from septic rats was accelerated twofold by the addition of IGF-I (10 nM) to perfusate. IGF-I increased the phosphorylation of translation repressor 4E-binding protein-1 (4E-BP1). Hyperphosphorylation of 4E-BP1 in response to IGF-I resulted in its dissociation from the inactive eukaryotic initiation factor (eIF) 4E.4E-BP1 complex. Assembly of the active eIF4F complex (as assessed by the association eIF4G with eIF4E) was increased twofold by IGF-I in the perfusate. In addition, phosphorylation of eIF4G and ribosomal protein S6 kinase-1 (S6K1) was also enhanced by IGF-I. Activation of mammalian target of rapamycin, an upstream kinase implicated in phosphorylating both 4E-BP1 and S6K1, was also observed. Thus the ability of IGF-I to accelerate protein synthesis during sepsis may be related to a stimulation of signaling to multiple steps in translation initiation with an ensuing increased phosphorylation of eIF4G, eIF4E availability, and S6K1 phosphorylation.

Effect of T3-induced hyperthyroidism on mitochondrial and cytoplasmic protein synthesis rates in oxidative and glycolytic tissues in rats

“…We tested whether three key regulatory elements of muscle protein synthesis, mTOR, p70 S6 kinase, and 4E-BP1, were activated by T 3 treatment (by measuring phosphorylation status), since this has not, to our knowledge, been previously reported. Phosphorylation of these molecules increases in response to anabolic stimuli, such as meals (13) or insulin-like growth factor I treatment (36), and decreases in response to catabolic conditions such as sepsis (15). We did not find differences between groups in phosphorylation of mTOR, p70 S6 kinase, and 4E-BP1 in skeletal muscles between groups.…”

Down-Regulation of Growth Signaling Pathways Linked to a Reduced Cotyledonary Vascularity in Placentomes of Over-Nourished, Obese Pregnant Ewes

“…Insulin/IGF-1 signaling exerts its biological effects mainly through activation of the PI3K/Akt signaling pathway [5-10]. The binding of insulin to its receptor leads to phosphorylation of insulin receptor substrate-1 (IRS-1), a key mediator of insulin signaling [6,7,11]. Phosphorylated IRS-1 recruits and activates PI3K/Akt signaling, which further activates mammalian target of rapamycin (mTOR) signaling [12].…”

Temporal changes in ERK phosphorylation are harmonious with 4E-BP1, but not p70S6K, during clenbuterol-induced hypertrophy in the rat gastrocnemius

“…Western blot analysis was performed at least twice for each protein of interest, and the results were averaged. With the exception of 4E-BP1, the ratio of phosphorylated/total proteins was used as the phosphorylation level, as was done previous reports (Vary 2006;Shi et al 2009;Kobayashi et al 2012). The phosphorylation status of 4E-BP1 was reported as the ratio of the ␥-form of 4E-BP1, as described elsewhere (Kimball et al 1997;Vary 2006).…”