Abstract 418: Perm1 is a Novel Regulator of Mitochondrial Energetics in Cardiomyocytes

Abstract

Mitochondrial oxidative metabolism and energy transduction pathways are critical for cardiac function. The expression of genes important for mitochondrial energetics is under the control of members of the peroxisome proliferator-activated receptor coactivator 1 (PGC-1) family and the estrogen-related receptor (ERR) subfamily. Perturbations in PGC-1 and/or ERR activities have been associated with impaired mitochondrial function and the development of heart failure. The mechanisms by which PGC-1 and ERR proteins regulate muscle specific transcriptional programs is not fully understood. P GC-1 and E RR-induced r egulator in m uscle 1 (Perm1) was recently identified in skeletal muscle as a muscle-specific key regulator of mitochondrial energetics. Although overexpression of Perm1 enhances oxidative capacity and fatigue resistance in mouse skeletal muscle, the underlying mechanisms remain to be elucidated. Perm1 is highly expressed in mouse and human hearts, and its expression level was reduced in pressure overload-induced heart failure in mice (49.9 ± 12.1% of sham, n=4, p<0.05) and in patients with heart failure (45.5 ± 12.1% of donors, n=5, p<0.05). Moreover, Perm1 is expressed in both the nucleus and the cytoplasm in primary cultured neonatal rat ventricular myocytes (NRVMs) and phenylephrine-induced cellular hypertrophy led to downregulation of Perm1 in both fractions (56.7 ± 1.7% of control). RNAseq followed by bioinformatic analysis revealed that siRNA-mediated Perm1 knockdown (KD) in NRVMs led to global downregulation of ERRα/PGC1α-target genes involved in oxidative phosphorylation, including the electron transport chain and TCA cycle ( Ndufs8; Ndufb8; Cox5a; Cox6a1; Coq2; Cox5a; Cox8a; Coq10b; Sdhb; Sdhd) . Basal respiration and ATP production rates were significantly reduced in Perm1-KD H9c2 rat ventricular myocyte-derived cells (60.4 ± 4.2% and 35.2 ± 8.8% of control cells that were transfected with scrambled-siRNA, both p<0.05). This study demonstrates a novel role of Perm1 in cardiomyocytes that provides an additional layer of mitochondrial energetics regulation, presumably in an ERRα- and PGC1α-mediated manner, and suggests that downregulation of Perm1 may contribute to mitochondrial impairment during heart failure.