Dystrophin glycoprotein complex‐associated Gβγ subunits activate phosphatidylinositol‐3‐kinase/Akt signaling in skeletal muscle in a laminin‐dependent manner

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Abstract
Previously, we showed that laminin‐binding to the dystrophin glycoprotein complex (DGC) of skeletal muscle causes a heterotrimeric G‐protein (Gαβγ) to bind, changing the activation state of the Gsα subunit. Others have shown that laminin‐binding to the DGC also leads to Akt activation. Gβγ, released when Gsα 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 Gβγ, using immunoprecipitation and immunoblotting, and purified Gβγ. 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 α‐dystroglycan, prevent PI3K‐binding to the DGC. Purified bovine brain Gβγ also caused PI3K and Akt activation. These results show that DGC‐Gβγ 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 β1 compared to normal muscle. This integrin binds laminin, Gβγ, and PI3K. Collectively, these suggest that PI3K is an important target for the Gβγ, 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‐Gβγ‐PI3K‐Akt signaling and is likely to be important to the pathogenesis of muscular dystrophy. Upregulating integrin β1 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. J. Cell. Physiol. 219: 402–414, 2009.