Inbred and genetically modified mice are frequently used to investigate the molecular mechanisms responsible for the beneficial adaptations to exercise training. However, published paradigms for exercise training in mice are variable, making comparisons across studies for training efficacy difficult. The purpose of this systematic review and meta-analysis was to characterize the diversity across published treadmill-based endurance exercise training protocols for mice and to identify training protocol parameters that moderate the adaptations to endurance exercise training in mice. Published studies were retrieved from PubMed and EMBASE and reviewed for the following inclusion criteria: inbred mice; inclusion of a sedentary group; and exercise training using a motorized treadmill. Fifty-eight articles met those inclusion criteria and also included a “classical” marker of training efficacy. Outcome measures included changes in exercise performance, V˙O2max, skeletal muscle oxidative enzyme activity, blood lactate levels, or exercise-induced cardiac hypertrophy. The majority of studies were conducted using male mice. Approximately 48% of studies included all information regarding exercise training protocol parameters. Meta-analysis was performed using 105 distinct training groups (i.e., EX-SED pairs). Exercise training had a significant effect on training outcomes, but with high heterogeneity (Hedges’ g=1.70, 95% CI=1.47–1.94, Tau2=1.14, I2=80.4%, prediction interval=−0.43–3.84). Heterogeneity was partially explained by subgroup differences in treadmill incline, training duration, exercise performance test type, and outcome variable. Subsequent analyses were performed on subsets of studies based on training outcome, exercise performance, or biochemical markers. Exercise training significantly improved performance outcomes (Hedges’ g=1.85, 95% CI=1.55–2.15). Subgroup differences were observed for treadmill incline, training duration, and exercise performance test protocol on improvements in performance. Biochemical markers also changed significantly with training (Hedges’ g=1.62, 95% CI=1.14–2.11). Subgroup differences were observed for strain, sex, exercise session time, and training duration. These results demonstrate there is a high degree of heterogeneity across exercise training studies in mice. Training duration had the most significant impact on training outcome. However, the magnitude of the effect of exercise training varies based on the marker used to assess training efficacy.

Exercise is used as a therapeutic option to improve an individual's quality of life or as a method to attenuate the severity of cardiovascular, respiratory, or metabolic‐related diseases. However, changes in cardiorespiratory fitness in response to endurance training are often heterogenous with individuals being more or less responsive to a similar exercise protocol. Heterogeneity in responses to exercise training is observed in humans and rodents. Low responses to training might be mitigated by modifying the standard exercise training protocol by altering the frequency, intensity, or duration of training. Threshold‐based exercise training prescription, e.g., critical speed, has also been proposed as a means to reduce the variability of training responses. The aim of this study was to identify the effect of different exercise training intensities on changes in exercise capacity in two inbred strains of mice, NZW/LacJ (NZW) and FVB/NJ (FVB). NZW mice were selected because they respond poorly to moderate intensity endurance exercise whereas, FVB mice respond well to endurance training. We hypothesized that increasing the intensity of the training would reduce the number of low or non‐responding NZW mice. To test this hypothesis, female mice from each strain were assigned to one of three treadmill training groups based on critical speed (CS): 80% of their critical speed (CS80%), 90% of their critical speed (CS90%), or sedentary controls (SED). Exercise groups within each strain were volume matched and thus ran the same distance over the 6‐week training period. Pre‐training exercise capacity differed between NZW (30.5 ± 3.5 min) and FVB (36.1 ± 2.8 min) mice (P < 0.001). Critical speeds also differed between strains (NZW: 25.1 ± 2.4 m/min; FVB: 32.9 ± 1.6 m/min, P < 0.001). After training, both FVB exercise groups, CS80% (10.0 ± 4.9 min, P = 0.004) and CS90% (14.0 ± 7.7 min, P = 0.007), improved their endurance capacity. In contrast, NZW CS80% did not significantly improve after training (0.4 ± 4.6 min), but NZW CS90% improved significantly (3.6 ± 2.7 min, P = 0.02). Collectively, these data indicate that the high‐responder FVB strain can adapt to moderate‐intensity and high‐intensity endurance training. The low‐responder NZW strain only showed significant improvement after sufficient homeostatic stress was induced through high‐intensity endurance training. These data suggest that increasing exercise intensity can improve responses to exercise training in low‐ or non‐responding mice.

Impaired endothelial function has been shown in SLE patients and lupus-prone mice. Emerging evidence supports impaired mitochondrial dynamics and mitophagy contribute to SLE and endothelial dysfunction. Spermidine is a natural polyamine that stimulates mitophagy by activating the PINK1-Parkin pathway and can improve endothelial function. However, the effect of spermidine on mitophagy and vascular function in SLE has not been explored. To address this gap, 9-week-old female lupus-prone (MRL/lpr) and healthy control (MRL/MpJ) mice were randomly assigned into one of two groups, spermidine treatment (Lpr T and MpJ T) or control (Lpr C and MpJ C). Treated mice received spermidine (3mM) via drinking water for 8 weeks. After 8 weeks of treatment, endothelium-dependent vasorelaxation to acetylcholine (ACh) and endothelium-independent vasorelaxation to sodium nitroprusside (SNP) were measured in thoracic aortas using a wire myograph. Maximal responses to ACh were significantly impaired in Lpr C (67.1 ± 8.7, n = 11) compared to Mp C (90.3 ± 3.1, n = 13) (p = 0.01). Spermidine improved endothelial function in thoracic aorta from Lpr T (90.3 ± 2.8, n = 13) compared to Lpr C (p = 0.03). Maximal responses to SNP were not significantly different across the groups. Thoracic and abdominal aortas were used for measurements of protein content (n = 3-4/group) and gene expression (n = 4/group), respectively. There were strain differences in the mRNA expression of endothelial nitric oxide synthase ( Nos3) between Lpr C (0.65 ± 0.14) and MpJ C (1.00 ± 0.16) (p = 0008). In MpJ mice, Nos3 mRNA expression was significantly higher in the aorta from the MpJ T (1.47 ± 0.39) compared to MpJ C (p = 0.04). No significant differences were found in the Nos3 expression between Lpr groups. Vascular cell adhesion molecule 1 (Vcam1) is an indicator of inflammation and is associated with atherosclerosis susceptibility. Protein content of Vcam1 was significantly lower in Lpr T (3.73 ± 0.61) compared to Lpr C (8.49 ± 2.58) (p = 0.04) and gene expression of Vcam1 was also lower in Lpr T compared to Lpr C, suggesting spermidine decreases the inflammatory responses in vessels from SLE mice. Protein content of Parkin was measured as a marker of mitophagy. Parkin was significantly lower in Lpr C (0.38 ± 0.61) compared to MpJ C (1.00 ± 0.09) (p = 0.004), suggesting lower mitophagy in aorta from SLE mice. Parkin content in Lpr T was similar to MpJ C. Collectively, these results demonstrate the beneficial effects of spermidine treatment on endothelial function in SLE mice and suggest inflammation and altered mitophagy contribute to endothelial dysfunction in SLE. 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.

An impaired endothelial function is a fundamental component of the pathogenesis of cardiovascular disease. In mice, exercise training is well‐known to improve cardiorespiratory fitness and endothelial function. However, the post exercise training effect on endothelial function varies among different strains of mice, suggesting that genetic background contributes to the heterogeneous effect of exercise on vascular health. NZW/LacJ (NZW) mice are known as relatively low responders to exercise training compared to high responder strains such as FVB/NJ (FVB). NZW mice also have relatively poor endothelial function in thoracic aorta when compared with other mouse strains. Therefore, we aimed to determine the contribution of genetic background to endothelial adaptation to exercise training in FVB and NZW mice. Vasoreactivity was assessed in femoral arteries from female mice from both strains (NZW and FVB) after 6 weeks of training using two different critical speed (CS) treadmill training intensities. Mice from each strain were randomly assigned to one of three groups: sedentary (SED), 80% of CS training (CS80), and 90% of CS (CS90) training. After training, endothelium‐dependent vasorelaxation to acetylcholine (ACh) and endothelium‐independent vasorelaxation to sodium nitroprusside (SNP) were measured as well as the vasocontractile responses to phenylephrine (PE) and potassium chloride (KCl). Maximal relaxation responses and IC50 for ACh and SNP were similar between NZW groups (SED, CS80, and CS90). In femoral arteries from FVB mice, there were no differences for maximal relaxation to ACh, but there was significant difference in IC50 for ACh‐induced vasorelaxation between SED vs. CS90 groups (p=0.05). Maximal responses to ACh were similar between NZW and FVB; however, IC50 was significantly lower in FVB compared with NZW, indicating that sensitivity to ACh is greater in arteries from FVB. There was a significant strain‐dependent difference for IC50 for SNP despite no strain differences for maximal responses. There was no effect of exercise or strain on contractile responses to PE and KCl, although the EC50 for KCl induced vasocontraction was higher (p=0.0329) in NZW. Treadmill exercise training at 80% or 90% CS did not contribute to improved vasomotor function in NZW while higher intensity exercise improved sensitivity to ACh in arteries from FVB. Genetic background did not significantly impact vasomotor function or endothelial responses to exercise training in FVB and NZW mice.