Lipoprotein receptor-related protein 6 (LRP6) binds to Wnt ligands to transduce signal by stabilization of β-catenin, which has been involved in the regulation of embryonic development and metabolism et al. Here, we observed LRP6 decreased in human hearts with dilated cardiomyopathy (DCM), and it also decreased in cultured cardiomyocytes under glucose- deprivation (GD). Knockdown of LRP6 greatly inhibited cell viability in cardiomyocytes under GD, but it didn't induce the effect in cardiomyocytes at baseline. Overexpression of LRP6 increased the cell viability in GD-cardiomyocytes. To explore potential molecular mechanisms, we detected the phosphorylation of dynamin-related protein 1(Drp1) and active β-catenin in cardiomyocytes under GD. Knockdown of LRP6 enhanced p-Drp1(S616) level while it didn't alter the p-Drp1(S637) and active β-catenin level in GD-cardiomyocytes. Drp1 inhibitor significantly suppressed the increase in p-Drp1 at S616 and improved the cell viability in GD-cardiomyocytes with knockdown of LRP6. Further analysis showed that knockdown of LRP6 also increased the phosphorylation of mammalian target of rapamycin (mTOR), and Drp1 inhibitor greatly inhibited the increase in p-mTOR level in GD-cardiomyocytes. The present study indicated that knockdown of LRP6 inhibited the cell viability by activation of Drp1 in GD-cardiomyocytes, and the phosphorylation of mTOR may be involved in the process. It suggests that LRP6 can prevent cardiomyocytes from death in nutrition-deprived condition.