FOXO3a mediates signaling cross‐talk that coordinates ubiquitin and atrogin‐1/MAFbx expression during muscle atrophy

Abstract

Muscle atrophy due to chronic diseases (e.g., diabetes) or glucocorticoid‐induced insulin resistance results from programmed changes in ubiquitin‐proteasome system (UPS) gene expression (i.e., atrogenes). Different signaling pathways regulate various atrogenes like ubiquitin and the muscle‐specific E3 ligase atrogin‐1/MAFbx. A novel signaling model was tested in which FOXO3a mediates cross‐talk between the PI3‐kinase (PI3K)/Akt and MEK/ERK pathways to coordinate the expression of atrogin‐1 (AT‐1) and ubiquitin C (UbC), respectively. In L6 myotubes, dexamethasone reduced IRS‐1 protein and PI3K/Akt signaling while increasing AT‐1 expression; IRS‐2 protein, MEK/ERK/Sp1 signaling and UbC transcription were simultaneously increased. Expression of constitutively‐activated FOXO3a or knockdown of IRS‐1 increased IRS‐2 protein, MEK/ERK signaling and UbC expression. In rat muscles undergoing atrophy due to streptozotocin‐induced insulin deficiency, Akt signaling was decreased whereas MEK/ERK signaling and expression of UbC and AT‐1 were increased. These results demonstrate that FOXO3a mediates a reciprocal communication between the PI3K/Akt and MEK/ERK pathways that coordinates AT‐1/MAFbx and ubiquitin expression, thereby supporting muscle atrophy. Supported by NIH DK50740 and DK61521.