Regulation of phosphatidylinositol 3-kinase (PI3K)/Akt and nuclear factor-kappa B signaling pathways in dystrophin-deficient skeletal muscle in response to mechanical stretch

✍ Scribed by Charu Dogra; Harish Changotra; Jon E. Wergedal; Ashok Kumar

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 472 KB
• Volume: 208
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/jcp.20696

✦ Synopsis

Abstract

Phosphatidylinositol 3‐kinase (PI3K)/Akt and nuclear factor‐kappa B (NF‐κB) signaling pathways play a critical role in mediating survival signals. In this study we have investigated how loss of dystrophin (the primary cause of Duchenne muscular dystrophy) modulates the activation of PI3K/Akt and NF‐κB signaling pathways in skeletal muscle in response to mechanical stimulation. Activation of Akt was significantly higher in diaphragm muscle from dystrophin‐deficient mdx mice compared to normal mice at both prenecrotic and necrotic states. Higher activation of Akt was also observed in cultured dystrophin‐deficient primary myotubes differentiated in vitro. Application of passive mechanical stretch ex vivo synergistically increased the activation of Akt in diaphragm of mdx mice. Stretch‐induced activation of PDK‐1 and PI3K were also higher in diaphragm of mdx mice compared to normal mice. Pretreatment of diaphragm with PI3K inhibitor LY294002 blocked the activation of Akt in normal and mdx mice. Higher activation of Akt was associated with increased phosphorylation of its downstream targets glycogen synthase kinase 3β (GSK3β), FKHR, and mammalian target of rapamycin (mTOR). Treatment of diaphragm muscle with LY294002 inhibited the stretch‐induced activation of IkappaB (IκB) kinase (IKK) and NF‐κB transcription factor in normal and mdx mice. Mechanical stretch also reduced the interaction of HDAC1 with RelA subunit of NF‐κB in diaphragm muscle. Finally, cellular levels of Bcl‐2, cIAP1, and integrin β1 and activation of integrin linked kinase were higher in diaphragm muscle of mdx mice compared to normal mice. Taken together, our data suggest that loss of dystrophin and/or mechanical stretch results in the up‐regulation of PI3K/Akt and NF‐κB signaling pathways in skeletal muscle. J. Cell. Physiol. 208: 575–585, 2006. © 2006 Wiley‐Liss, Inc.