Author(s): HAYDEN, C., ROSHANRAVAN, B., BAAR, K., Institution: UNIVERSITY OF CALIFORNIA DAVIS, Country: UNITED STATES, Abstract-ID: 2237

INTRODUCTION:
Chronic kidney disease (CKD) is associated with muscle wasting and poor exercise capacity. Exercise and nutritional interventions can improve both musculoskeletal function and kidney health in CKD. The difficulty, cost, and burden of this type of intervention, however, limits research throughput and the exploration of novel interventions. For this reason, we characterized a rat model of CKD to enable mechanistic understanding of how exercise alters physiological and molecular function in CKD.
METHODS:
Female Sprague-Dawley rats (n=16, age=7wk) were evaluated for exercise tolerance by measuring maximal speed reached during an incremental treadmill run (10m/min + 2m/min every 3 min at a 10° incline) to volitional fatigue (sitting on the electrical grid > 5s). Plantar flexor muscle function was assessed under anesthesia using needle electrode stimulation (30mA) of the gastrocnemius muscle and a force transducer. Maximal strength was evaluated using a force-frequency curve from (20-200Hz) and fatigue through 180 repeated stimulations with 2s between contractions (70Hz, duration 0.350s). Animals were divided to equate exercise tolerance into a control group (CON, n=8) and a group that was fed a diet containing 0.25% adenine to induce kidney disease (CKD, n=8). Following 8wks on diet, performance measures were reassessed. Pooled time effects were measured via ANOVA. Effect sizes (post value – baseline value) were calculated for each group and compared by t-test.
RESULTS:
After 8 weeks on 0.25% adenine diet rats presented with elevated creatinine (1.16 vs 0.57mg/dL, p=0.01), blood urea nitrogen (56.6 vs 21.3mg/dL, p=0.004), kidney mass (1.62 vs 0.86g, p<0.001), and lower hematocrit levels (37.4 vs 48.5%, p<0.001), mirroring human CKD. Final body weight did not differ (CKD vs CON, 282 vs 284g, p=0.9). Collectively both groups had decreased exercise tolerance (mean of 27 to 21 m/min, p=0.009), increased maximal plantar flexion torque (73 to 107mNm, p<0.001), and increased muscle fatigue (32 to 24% of initial force, p=0.003) over 8wk. Maximal plantar flexor force increased significantly more in CON than in the CKD group (difference between effect size =14.9mNm, p=0.0494) and there was a trend towards a greater increase in muscle fatigue in the CKD rats (-8% of initial force, p=0.098). There was no difference in the effect size on exercise tolerance (p=0.427). Interestingly, the soleus muscle of CKD rats was larger than CON (0.47 vs 0.41mg/g body weight, p=0.005), and in the CKD group alone the left kidney was larger than the right (1.87 vs 1.37g, p<0.0001).
CONCLUSION:
Females are understudied in both animal and human CKD research and sex has been shown to augment the development of pathology in CKD. These results demonstrate that 8wks of adenine feeding leads to pathologic signs of CKD in young female rats and suggest that muscle dysfunction has begun to develop during this time. Longer interventions may be necessary to better model human musculoskeletal pathology in female rats.