ZSF1 lean rats – How healthy are they?

Abstract

ZSF1 lean rats are widely used as controls in cardiometabolic studies involving ZSF1 obese rats, which develop a cardiometabolic syndrome and diastolic dysfunction at a young age due to a double leptin receptor mutation (Lepr^cp and Lepr^fa). Although, lean littermates show no overt signs of cardiometabolic disease or diastolic impact, they belong to one of three genotypic variants, two of which carry one of the mutant Lepr alleles and, thus, doubt has been raised about their suitability as healthy controls. We compared 32-week-old female ZSF1 lean and Wistar rats regarding physiological, myocardial, vascular, skeletal muscle, and mitochondrial characteristics. Lean rats showed lower body weight but increased heart, kidney, and skeletal muscle mass. Despite thicker ventricular walls, systolic and diastolic function were preserved. Hemodynamically measured contractility was higher as underpinned by a higher mitochondrial respiratory capacity of LV fibers. However, left ventricular filling pressure was elevated, accompanied by increased ventricular stiffness. Endothelial function was preserved, but smooth muscle responsiveness was reduced, indicated by impaired SNP-induced relaxation. Passive vascular stiffness mediated by collagenous fibers was significantly higher in lean rats. Skeletal muscle function was mostly preserved, though maximal specific force of the EDL was reduced. Taken together, ZSF1 lean rats are physiologically different from Wistar rats as they display enlarged myocardial dimensions accompanied by increased blood pressure and an incipient diastolic and vascular stiffness. Therefore, our data indicate an early phase of passive compliance disorder in ZSF1 lean animals, which might become more pronounced at an advanced age.

Keywords

cardiovascular function / HFpEF / HFpEF rat model / skeletal muscle function / ZSF1 lean rat

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2025 The Author(s). Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.