Bidirectional regulation of upstream IGF-I/insulin receptor signaling and downstream FOXO1 in cardiomyocytes

Abstract

Signaling pathways of IGF-I and insulin receptors play important roles in the regulation of myocardial function. FOXO1 is a member of the forkhead transcriptional factor family, but how insulin and IGF-I receptor signaling regulate FOXO1 in cardiomyocytes is not well understood. This study was carried out to elucidate how IGF-I and insulin receptor signaling modulate FOXO1 in cardiomyocytes. In cardiomyocytes, activation of IGF-I receptor and insulin receptor lead to rapid phosphorylation of FOXO1. Inhibition of phosphatidylinositol 3-kinase/Akt pathway suppressed the effect of insulin and IGF-I on FOXO1 phosphorylation. Prolonged incubation with IGF-I increased ubiquitination of FOXO1 and downregulated the abundance of FOXO1 proteins, which suggested that IGF-I might modulate FOXO1 degradation. To explore whether FOXO1 could modulate IGF-I and insulin signaling, a constitutively active FOXO1 was overexpressed in cardiomyocytes. The abundance of insulin receptor and IGF-I receptor was significantly upregulated in the cells overexpressing active FOXO1, accompanied by increased receptor phosphorylation upon insulin/IGF-I stimulation. Interestingly, overexpression of constitutively active FOXO1 also led to activation of MEK and Akt phosphorylation. IGF-I-stimulated MEK and Akt phosphorylation were augmented by overexpression of constitutively active FOXO1. These findings indicate bidirectional regulation of insulin/IGF-I receptor signaling and FOXO1 in cardiomyocytes. FOXO1 may provide feedback control through upregulation of insulin and IGF-I receptor signaling.

Computational modelling of the regulation of Insulin signalling by oxidative stress

“…The result of this is to increase the sensitivity to insulin; as shown in the right-hand panel, the insulin dose–response curve then moves appreciably to lower concentrations. The upregulation of the insulin receptor has been shown qualitatively in C2C12 cells [74] and the twofold upregulation is in agreement with experiments in which FOXO is overexpressed in rat cardiomyocytes [53]. For SOD2, regulated similarly, there is qualitative data from MEFs and DL23 cells [60].…”

High Dietary Fat Selectively Increases Catalase Expression within Cardiac Mitochondria

“…FOXO3-dependent catalase induction has been demonstrated in response to oxidative stress-mediated hypertrophy of rat cardiomyocytes (55). Additionally, treatment of rat cardiomyocytes with insulin leads to increased phosphorylation, ubiquitination, and eventual down-regulation of FOXO1 (56). Altogether, these data suggest that JNK activation by H 2 O 2 promotes insulin resistance and FOXO-mediated transactivation of antioxidant genes, including catalase.…”

Salmonid genomes have a remarkably expandedakirinfamily, coexpressed with genes from conserved pathways governing skeletal muscle growth and catabolism

“…Other details are as described in Fig. 2. tions [31][32][33][34][35][36][37][38]. Comparing Akirin2(1) and 2(2), only 2 of 198 (ϳ1%) positions were type II sites (positions 94 -95) and these were not located proximally to any predicted phosphorylated residues (Fig.…”

“…Mammalian Mafbx is also an essential component of proteosome-mediated atrophy of skeletal muscle and is activated by p38-MAPK signaling (23), but not by NF-B (11). The expression of both Mafbx and Murf1 is also regulated by FoxO transcription factors in mammalian skeletal muscle (23), as is the IGF-I receptor in cardiomyocytes (36). Thus it is possible that the coexpression of cluster 1 genes reflects the cumulative activation (during fasting) or repression (during feeding) of more than one pathway mediating catabolism.…”