Abstract
Functional assessments of cardiovascular fitness (CVF) are needed to establish animal models of dysfunction, test the effects of novel therapeutics, and establish the cardio-metabolic phenotype of mice. In humans, the graded maximal exercise test (GXT) is a standardized diagnostic for assessing CVF and mortality risk. These tests, which consist of concurrent staged increases in running speed and inclination, provide diagnostic cardio-metabolic parameters, such as, VO2max, anaerobic threshold, and metabolic crossover. Unlike the human-GXT, published mouse treadmill tests have set, not staged, increases in inclination as speed progress until exhaustion (PXT). Additionally, they often lack multiple cardio-metabolic parameters. Here, we developed a mouse-GXT with the intent of improving mouse-exercise testing sensitivity and developing translatable parameters to assess CVF in healthy and dysfunctional mice. The mouse-GXT, like the human-GXT, incorporated staged increases in inclination, speed, and intensity; and, was designed by considering imitations of the PXT and differences between human and mouse physiology. The mouse-GXT and PXTs were both tested in healthy mice (C57BL/6J, FVBN/J) to determine their ability to identify cardio-metabolic parameters (anaerobic threshold, VO2max, metabolic crossover) observed in human-GXTs. Next, theses assays were tested on established diet-induced (obese-C57BL/6J) and genetic (cardiac isoform Casq2-/-) models of cardiovascular dysfunction. Results showed that both tests reported VO2max and provided reproducible data about performance. Only the mouse-GXT reproducibly identified anaerobic threshold, metabolic crossover, and detected impaired CVF in dysfunctional models. Our findings demonstrated that the mouse-GXT is a sensitive, non-invasive, and cost-effective method for assessing CVF in mice. This new test can be used as a functional assessment to determine the cardio-metabolic phenotype of various animal models or the effects of novel therapeutics.
Highlights
Obesity rates are rising exponentially and increase patients’ risks for developing cardiovascular diseases [1]
Our goal was to develop a test for mice that provided cardio-metabolic parameters previously reported in the human Human graded maximal exercise test (GXTh) and to compare those parameters describing mouse performance during both the Mouse graded maximal exercise test (GXTm) and PXTm
Within-subjects design for PXTm and GXTm was used to reduce errors associated with individual differences
Summary
Obesity rates are rising exponentially and increase patients’ risks for developing cardiovascular diseases [1]. For over 50 years, human research has used graded maximal exercise testing (GXTh) as the prototypical method to study cardiovascular and metabolic responses of the body to stress [2,3,4] These standardized GXTh tests, such as the gold standard Bruce protocol [5, 6], are key non-invasive and cost-effective methods for the assessing patient mortality risks [7, 8] and diagnosing coronary artery disease (CAD) [9]. Some knockout models are generated from mutations observed in patients with impaired cardiovascular function These mouse models often phenocopy human mutations, develop cardiac dysfunction, and can be used to generate highly translatable findings.
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