Abstract 11928: Perm1 Promotes Cardiomyocyte Mitochondrial Biogenesis and Protects Against Hypoxia/Reoxygenation-Induced Damage in Mice

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Introduction: Dysregulation of cardiac energy metabolism can result in immature heart development and disrupt the ability of the adult myocardium to adapt to stress, potentially leading to heart failure. In contrast, restoration of abnormal mitochondrial function can have beneficial effects on cardiac dysfunction. Previously, we identified a novel protein termed Perm1 (PGC-1 and ERR induced regulator, muscle 1) that is enriched in skeletal and cardiac muscle and transcriptionally regulated by PGC-1 (Peroxisome proliferator-activated receptor gamma coactivator 1) and ERR (Estrogen-related receptor). The role of Perm1 in the heart is poorly understood and was studied here. Hypothesis: We hypothesize that Perm1 plays a crucial role in cardiac metabolism and ischemic injury. Methods: To directly study the effect of Perm1 on cardiomyocyte oxidative metabolism, Perm1 or LacZ (control) was expressed in mouse neonatal cardiomyocytes (NCM) using an adenovirus system. We analyzed genes and proteins that play essential roles in cardiac metabolism. NCM were also subjected to hypoxia/reoxygenation (H/R). Finally, to study the mechanism underlying Perm1’s action, we investigated the effect of Perm1 on the activity of ERR and the interaction of Perm1 and PGC-1α. Results: Cardiac Perm1 expression was down-regulated in mice with heart failure and human patients with dilated cardiomyopathy. Perm1 selectively regulated PGC-1/ERR targets, such as Ckmt2 and Sirt3. Perm1 interacted with PGC-1α, enhanced activation of PGC-1 and ERRs, and increased recruitment of PGC-1α to the target gene promoters (Ckmt2 and Sirt3), possibly creating a feedforward loop of Perm1 and PGC-1α/ERRs. Perm1 also increased mitochondrial DNA copy number and augmented oxidative capacity in NCM. Moreover, we found that Perm1 reduced cellular damage induced by H/R and mitigated cell death in cardiomyocytes. Conclusions: Perm1 promotes mitochondrial biogenesis in mouse cardiomyocytes through PGC-1/ERR and protects cellular damage induced by H/R. Future studies can assess the potential of Perm1 to be used as a novel therapeutic to restore cardiac dysfunction caused by ischemic injury. An NIH grant, R01HL151239, supports this work (To Y. C. and R. S. R.).