Activation of Gα_q in Cardiomyocytes Increases Vps34 Activity and Stimulates Autophagy

Receptors that activate the heterotrimeric G protein Gα_q are thought to play a role in the development of heart failure. Dysregulation of autophagy occurs in some pathological cardiac conditions including heart failure, but whether Gα_q is involved in this process is unknown. We used a cardiomyocyte-specific transgenic mouse model of inducible Gα_q activation (termed Gα_qQ209L) to address this question. After 7 days of Gα_q activation, Gα_qQ209L hearts contained more autophagic vacuoles than wild type hearts. Increased levels of proteins involved in autophagy, especially p62 and LC3-II, were also seen. LysoTracker staining and western blotting showed that the number and size of lysosomes and lysosomal protein levels were increased in Gα_qQ209L hearts, indicating enhanced lysosomal degradation activity. Importantly, an autophagic flux assay measuring LC3-II turnover in isolated adult cardiomyocytes indicated that autophagic activity is enhanced in Gα_qQ209L hearts. Gα_qQ209L hearts exhibited elevated levels of the autophagy initiation complex, which contains the Class III phosphoinositide 3-kinase Vps34. As a consequence, Vps34 activity and phosphatidylinositol 3-phosphate levels were higher in Gα_qQ209L hearts than wild type hearts, thus accounting for the higher abundance of autophagic vacuoles. These results indicate that an increase in autophagy is an early response to Gα_q activation in the heart.