Phosphatase and tensin homolog (PTEN) deleted from chromosome 10 has been implicated in the maintenance of cardiac homeostasis although the underlying mechanism(s) remains elusive. We generated a murine model of cardiomyocyte-specific knockout of PTEN to evaluate cardiac geometry and contractile function, as well as the effect of metformin on PTEN deficiency-induced cardiac anomalies, if any. Cardiac histology, autophagy and related signaling molecules were evaluated. Cardiomyocyte-specific PTEN deletion elicited cardiac hypertrophy and contractile anomalies (echocardiographic and cardiomyocyte contractile dysfunction) associated with compromised intracellular Ca(2+) handling. PTEN deletion-induced cardiac hypertrophy and contractile anomalies were associated with dampened phosphorylation of PTEN-inducible kinase 1 (Pink1) and AMPK. Interestingly, administration of AMPK activator metformin (200mg/kg/d, in drinking H2O for 4weeks) rescued against PTEN deletion-induced geometric and functional defects as well as interrupted autophagy and autophagic flux in the heart. Moreover, metformin administration partially although significantly attenuated PTEN deletion-induced accumulation of superoxide. RNA interference against Pink1 in H9C2 myoblasts overtly increased intracellular ATP levels and suppressed AMPK phosphorylation, confirming the role of AMPK as a downstream target for PTEN-Pink1. Further scrutiny revealed that activation of AMPK and autophagy using metformin and rapamycin, respectively, rescued against PTEN deletion-induced mechanical anomalies with little additive effect. These data demonstrated that cardiomyocyte-specific deletion of PTEN leads to the loss of Pink1-AMPK signaling, development of cardiac hypertrophy and contractile defect. Activation of AMPK rescued against PTEN deletion-induced cardiac anomalies associated with restoration of autophagy and autophagic flux. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.