Differential Cardiovascular and Mitochondrial Adaptations in Humanized P53 R72P Knock-In Mice: 2390 Board #54 May 31 9:30 AM - 11:00 AM

We previously demonstrated that tumor suppressor p53 plays a crucial role in mitochondrial biogenesis and mtDNA quality control by transcriptional regulation of mitochondrial transcription factor A (TFAM) gene. Human P53 gene contains a common polymorphism at codon 72 (p53R72P), which has been shown to be associated with mitochondrial integrity and their function. PURPOSE: Here, we investigate whether p53Arg72Pro is associated with exercise response with respect to cardiovascular and mitochondrial functions using humanized p53 knock-in mouse model. METHODS: Humanized P53 Knock-In mice (HUPKI) containing either the human version of P53R72 or P53P72 genes were randomly assigned to sedentary or a 9-week voluntary wheel running exercise (VW) group. Angiotensin II (1 mg/kg/day) was infused for 4 weeks before mice were euthanized. Maximal aerobic capacity was measured by a motorized treadmill running test. Blood pressure was measured using a radio-telemetry apparatus. Muscle mtDNA copy number was measured by qPCR. Muscle capillary density was measured by immunostaining. RESULTS: Aerobic exercise capacity was similar between R72 HUPKI vs P72 HUPKI in sedentary group. However, R72 HUPKI showed greater aerobic exercise capacity compared to P72 HUPKI mice in VW group compared to the R72 HUPKI (R72, 2584.2±536.0 vs. P72, 2015.3± 359.4, sec, p=0.004). In the skeletal muscle, mtDNA content (P72, 0.98±0.28 vs. R72, 1.49±0.18, p= 0.007) and capillary density (R72, 4.2±0.3 vs P72, 3.4±0.4, p=0.006) were significantly higher in R72 HUPKI compared to P72 HUPKI in VW group (p <0.05). In addition, R72 HUPKI showed significantly greater reduction in blood pressure after VW compared to P72 HUPKI (MAP, R72: 114.9±9.5 vs. P72: 128.5±17.9, mmHg, p=0.006). CONCLUSION: Data suggest that p53 codon 72 arginine allele may have a greater cardiovascular and mitochondrial adaptations to aerobic exercise training. Supported by NIH Grant R01 HL126952