Outbred, UM-HET3 mice have greater metabolic and arterial function than inbred, C57BL/6J mice
Authors: Machin Daniel , Berg Sen Jennifer , Li Zhuoxin , Sabouri Mostafa , Deacon Christina , Bernardo Joseph , Zheng Xiangyu 
Published: May 2023

In recent years, UM-HET3 mice have become more commonly used in biomedical research. UM-HET3 mice are an outbred, genetically diverse strain of mice that is produced by crossing four inbred strains: BALB/cByJ, C57BL/6J, C3H/HeJ, and DBA/2J. Notably, the UM-HET3 strain is used by the National Institute on Aging Interventions Testing Program to investigate treatments that may extend lifespan and delay disease/dysfunction, while minimizing the impact of strain-specific phenotypes that might be observed in inbred, genetically identical strains like the C57BL/6J strain of mice. Here, we sought to examine phenotypic differences between age-matched male and female inbred, C57BL/6J and outbred, UM-HET3 mice (age: 6.4±0.0 mo, n=16 [8M/8F] per group). UM-HET3 had a greater body mass (C57BL/6J: 27±1 vs. UM-HET3: 32±1 g, P<0.05) and tibial length (C57BL/6J: 18.1±0.2 vs. UM-HET3: 19.6±0.3 mm, P<0.05) than C57BL/6J mice. Despite larger body stature, UM-HET3 mice had lower fasting blood glucose (C57BL/6J: 192±6 vs. UM-HET3: 168±5 mg/dL, P<0.05) and lower glucose area under the curve (AUC) in response to glucose tolerance testing (C57BL/6J: 34±1 vs. UM-HET3: 28±2 AU, P<0.05). On the contrary, there were no strain-related differences in glucose AUC in response to insulin tolerance testing (C57BL/6J: 14±1 vs. UM-HET3: 14±1 AU, P>0.05). We also observed no differences in systolic blood pressure (C57BL/6J: 115±2 vs. UM-HET3: 114±2 mmHg, P>0.05), although aortic stiffness, determined by pulse wave velocity (PWV), was lower in UM-HET3 compared to C57BL/6J mice (C57BL/6J: 309±5 vs. UM-HET3: 255±4 cm/sec, P<0.05). Endothelium-dependent dilation (EDD), determined by ex vivo maximal carotid artery dilation to acetylcholine (ACh), was lower in C57BL/6J compared to UM-HET3 (C57BL/6J: 84±2 vs. UM-HET3: 90±1%, P<0.05). In the presence of the nitric oxide (NO) synthase inhibitor, L-NAME, maximal dilation to ACh was similar between groups (C57BL/6J: 38±4 vs. UM-HET3: 34±4%, P>0.05). Thus, NO-mediated dilation, determined by subtracting ACh+L-NAME maximal dilation from ACh maximal dilation, was higher in UM-HET3 compared to C57BL/6J mice (C57BL/6J: 45±3 vs. UM-HET3: 57±4%, P<0.05). We observed no differences in endothelium-independent dilation, determined by ex vivo maximal dilation to sodium nitroprusside (C57BL/6J: 87±1 vs. UM-HET3: 90±2%, P>0.05). In summary, C57BL/6J mice appear to be smaller in stature, but with worse glucose handling, as indicated by impaired fasting glucose and glucose tolerance, compared to UM-HET3 mice. There are also strain differences in arterial function, as aortic stiffness was higher and EDD was lower in C57BL/6J compared to UM-HET3 mice. Strain differences in EDD appear to be due to a reduction in NO-mediated dilation in C57BL/6J mice. Collectively, these data suggest that there are phenotypic differences between these strains, indicating worse metabolic and arterial function in inbred, C57BL/6J compared to outbred, UM-HET3 mice. This study was funded in part by a grant from the National Institutes of Health (R00 AT010017). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.