Abstract 289: Perm1 is a Novel Regulator of Cardiac Energetics and Function

Regulation of mitochondrial energetics is key to maintain cardiac function. Perm1 ( P GC-1 and E RR- r egulator, m uscle 1 ) was previously shown to enhance exercise endurance in skeletal muscle through increasing mitochondrial bioenergetics. Despite the significant expression levels of Perm1 in the heart, its role in the healthy and diseased hearts has never been investigated. We found that cardiac Perm1 was downregulated in the mouse failing heart subjected to pressure overload for 4 weeks (24.4 ± 5.9 % of sham operated, p<0.05) and in patients with advanced heart failure (55.2 ± 13.1 % of donors, p<0.05) suggesting a role of Perm1 in cardiac pathology. Phenylephrine (PE)-induced hypertrophy in cardiomyocytes was accompanied by downregulation of Perm1 (55.7 ± 5.7 % of control, p <0.05), and adenovirus-mediated overexpression of Perm1 rescued PE-induced downregulation of estrogen-related receptor alpha (ERRα), a key transcriptional regulator of mitochondrial energetics, and its target gene, Ndufv1 (Complex I), suggesting that downregulation of Perm1 contributes to the development of mitochondrial dysfunction in response to hypertrophic stimuli. Pathway enrichment analysis in cardiomyocytes where Perm1 was knocked-down by siRNA (siPerm1) revealed that the most downregulated pathway was metabolism, while upregulated pathways were mostly related to synthesis and assembly of collagen fibrils (i.e. Col3a1, Col5a1, Col11a1, Lox). Cell stress test using Seahorse XF analyzer showed that basal respiration and ATP production were significantly reduced in siPerm1 cardiomyocytes (40.7 % and 23.6 % of scrambled-siRNA, respectively, both p <0.05). Luciferase reporter gene assay further revealed that Perm1 dose-dependently increased the promoter activity of the ERRα gene and known targets of ERRα, Ndufv1 and Ndufs1 (Complex I). Furthermore, systemic Perm1-knockout mice developed heart failure (3 months old ejection fraction 38.8 %), concurrent with downregulation of proteins involved in oxidative phosphorylation, such as Ndufaf4 and Uqcr11 (-6.14 and -2.39 in fold change, respectively), and increased fibrosis. These results suggest that Perm1 is a novel regulator of cardiac metabolism and function, that enhances energetics and suppresses fibrosis.