Dystrophin Glycoprotein Complex-Associated Gβγ Subunits Activate Phosphatidylinositol-3-Kinase/Akt Signaling in Skeletal Muscle in a Laminin-Dependent Manner

Previously, we showed that laminin-binding to the dystrophin glycoprotein complex (DGC) of skeletal muscle causes a heterotrimeric G-protein (G alpha beta gamma) to bind, changing the activation state of the Gs alpha subunit. Others have shown that laminin-binding to the DGC also leads to Akt activation. G beta gamma, released when Gsa is activated, is known to bind phosphatidylinositol-3-kinase (PI3K),which activates Akt in other cells. Here, we investigate whether muscle Akt activation results from G beta gamma, using immunoprecipitation and immunoblotting, and purified G beta gamma. In the presence of laminin, PI3K-binding to the DGC increases and Akt becomes phosphorylated and activated (pAkt), and glycogen synthase kinase is phosphorylated. Antibodies, which specifically block laminin-binding to alpha-dystroglycan, prevent PI3K-binding to the DGC. Purified bovine brain G beta gamma also caused PI3K and Akt activation. These results show that DGC-G beta gamma is binding PI3K and activating pAkt in a laminin-dependent manner. Mdx mice, which have greatly diminished amounts of DGC proteins, display elevated pAkt signaling and increased expression of integrin P I compared to normal muscle. This integrin binds laminin, G beta gamma, and PI3K. Collectively, these suggest that PI3K is an important target for the G beta gamma, which normally binds to DGC syntrophin, and activates PI3K/Akt signaling. Disruption of the DGC in mdx mouse is causing dis-regulation of the laminin-DGC-G beta gamma-PI3K-Akt signaling and is likely to be important to the pathogenesis of muscular dystrophy. Upregulating integrin beta 1 expression and activating the PI3K/Akt pathway in muscular dystrophy may partially compensate for the loss of the DGC. The results suggest new therapeutic approaches to muscle disease.