Analysis of systolic cardiac function in PERM1-knockout mice using large cohorts of animals

Several groups have demonstrated that PERM1 is a positive regulator of mitochondrial bioenergetics in the heart. However, conflicting results have emerged regarding whether PERM1 loss of function affects cardiac contractility. Here, we present data from a retrospective study compiling echocardiography data from all Perm1-knockout (Perm1-KO) mice and their wild-type (WT) littermates used for various molecular biology experiments in our laboratory between April 2022 and September 2023. This yielded an atypically large number of subjects per group-84 WT mice and 88 Perm1-KO mice. We analyzed echocardiography-derived parameters of left ventricular (LV) systolic function. The ejection fraction (EF) was 65.43 ± 7.13% in WT vs. 53.98 ± 8.80% in Perm1-KO mice (p = 5.21E-17, unpaired t-test). Other parameters showing statistically significant differences between WT and Perm1-KO (p < 0.05) included LV fractional shortening, LV diastolic and systolic diameters, LV anterior and posterior systolic wall thickness, LV posterior wall systolic thickening, stroke volume, and cardiac output. Importantly, this large cohort of echocardiography analyses revealed a broad range of cardiac contractile function among WT mice, and this degree of variability persisted in Perm1 KO; however, the entire distribution was shifted downward, suggesting that Perm1 deficiency reduces mean cardiac performance without altering intrinsic variability. Overall, our study indicates that constitutive Perm1 deletion leads to reduced contractility partially compensated by increased LV circumference. This study provides strong evidence that Perm1-KO causes specific remodeling of cardiac contractile function and provides a retrospective power analysis to guide future prospective studies.