PI3K/Akt signaling pathway contributes to the activation of NF‐kappaB transcription factor in dystrophin‐deficient skeletal muscles in response to mechanical stress

Abstract

PI3K/Akt signaling pathway plays a critical role in mediating survival signals in different cell types. Here, we investigated the activation of PI3K/Akt signaling pathway in diaphragm muscles of normal and dystrophin-deficient mdx mice in response to mechanical stress. Application of mechanical stress increased the activation of Akt kinase in normal and mdx muscle fibers. However, the basal level as well as mechanical stress-induced activation of Akt was higher in diaphragm muscle of mdx mice compared to age-matched control mice. Activation of Akt was associated with increased activation of several downstream phosphorylation targets such as GSK3-β, FKHR and m-TOR. Basal level of activation of NF-κB transcription factor was also higher in diaphragm muscle of mdx mice, which was further augmented by application of mechanical stress. Additionally, the level of NF-κB-regulated pro-survival molecules Bcl-2 and cIAP-1 was higher in diaphragm muscle of mdx mice compared to normal mice. Pretreatment of diaphragm muscle with LY294002 (an inhibitor of PI3K) blocked the activation of Akt and inhibited the DNA-binding activity of NF-κB transcription factor in both normal and mdx mice. Taken together our data suggest that PI3K/Akt signaling pathway contributes to the activation of NF-κB transcription factor in dystrophin-deficient skeletal muscles in response to mechanical stress.