FOXO3a mediates signaling crosstalk that coordinates ubiquitin and atrogin‐1/MAFbx expression during glucocorticoid‐induced skeletal muscle atrophy

Abstract

Muscle atrophy is a consequence of chronic diseases (e.g., diabetes) and glucocorticoid-induced insulin resistance that results from enhanced activity of the ubiquitin-proteasome pathway. The PI3K/Akt pathway inhibits the FOXO-mediated transcription of the muscle-specific E3 ligase atrogin-1/MAFbx (AT-1), whereas the MEK/ERK pathway increases Sp1 activity and ubiquitin (UbC) expression. The observations raise a question about how the transcription of these atrogenes is synchronized in atrophic muscle. We tested a signaling model in which FOXO3a mediates crosstalk between the PI3K/Akt and MEK/ERK pathways to coordinate AT-1 and UbC expression. In rat L6 myotubes, dexamethasone (> or = 24 h) reduced insulin receptor substrate (IRS)-1 protein and PI3K/Akt signaling and increased AT-1 mRNA. IRS-2 protein, MEK/ERK signaling, Sp1 phosphorylation, and UbC transcription were simultaneously increased. Knockdown of IRS-1 using small interfering RNA or adenovirus-mediated expression of constitutively activated FOXO3a increased IRS-2 protein, MEK/ERK signaling, and UbC expression. Changes in PI3K/Akt and MEK/ERK signaling were recapitulated in rat muscles undergoing atrophy due to streptozotocin-induced insulin deficiency and concurrently elevated glucocorticoid production. IRS-1 and Akt phosphorylation were decreased, whereas MEK/ERK signaling and expression of IRS-2, UbC and AT-1 were increased. We conclude that FOXO3a mediates a reciprocal communication between the IRS-1/PI3K/Akt and IRS-2/MEK/ERK pathways that coordinates AT-1 and ubiquitin expression during muscle atrophy.

DNA Methyltransferase 3a and Mitogen-activated Protein Kinase Signaling Regulate the Expression of Fibroblast Growth Factor-inducible 14 (Fn14) during Denervation-induced Skeletal Muscle Atrophy

“…Because binding of SP1 to Fn14 promoter is increased in denervated skeletal muscle, it is possible that activation of ERK5 stimulates SP1 activity, leading to the increased expression of Fn14. Previous studies have demonstrated that SP1 also gets activated and plays an important role in muscle atrophy in response to dexamethasone treatment (49,50). SP1 binds to promoter region and augments gene expression of ubiquitin, leading to increased activation of ubiquitinproteasome system.…”

Effect of insulin on dexamethasone-induced ultrastructural changes in skeletal and cardiac muscle

“…According to some researches for mammals, excessive glucocorticoids causing skeletal muscle atrophy in avian might be due to: (1) promoting proteolysis in muscle by stimulating the expression of proteins such as E3-ligases, atrogin-1, MuRF-1 (muscle ring finger 1), and the lysosomal enzyme cathepsin L in the ubiquitinproteolytic pathways (Auclair et al 1997;Hasselgren 1999;Marinovic et al 2002;Combaret et al 2005;Baehr et al 2010); (2) limiting the protein synthesis by inhibiting the transport of amino acids into the muscle and inhibiting the stimulatory action of insulin, IGF-I (insulin-like growth factor-I), and amino acids on the phosphorylation of eIF4E-binding protein 1 (4E-BP1) and the ribosomal protein S6 kinase 1 (S6K1) (Shah et al 2000a, b;Liu et al 2004;Schakman et al 2008b). In addition, the upregulation of myostatin and FOXO and the downregulation of IGF-I and myogenin might take part responsibility for the dexamethasone-induced skeletal muscle atrophy in chick according to some researches for mammals in vitro as well in vivo (Lang et al 2001;Ma et al 2001Ma et al , 2003Sandri et al 2004;Gilson et al 2007;Du et al 2007;Schakman et al 2008b;Zheng et al 2010). However, the ultrastructural results in our study showed that the diminishment in skeletal muscle size was not only attributed to the dwindlement of myofibrils but to the decreases of glycogen granules, lipids and other components in in-termyofibrillar and interfilamentary spaces.…”

XIAP Reduces Muscle Proteolysis Induced by CKD

“…Reduced FoxO activity could also account for the decrease in ubiquitin mRNA, because we recently found that FoxO indirectly regulates ubiquitin transcription. 51 Interestingly, Akt also phosphorylates XIAP at Ser-87. 52 The modification prevents the ubiquitination and subsequent degradation of XIAP; therefore, XIAP could be creating a positive-feedback loop to maintain its protein level and promote muscle cell survival by increasing Akt signaling.…”