The MDM2 SNP309 differentially impacts cardiorespiratory fitness in young healthy women and men

PURPOSE: Maximal oxygen consumption (VO₂max), the predominant index of cardiorespiratory fitness (CRF), is a predictor of whole-body function and longevity in humans. The central cardiac function and the skeletal muscle's capacity to use oxygen are key determinants of VO₂max. Murine Double Minute 2 (MDM2), mainly known as an oncogene, could regulate myocardial hypertrophy, skeletal muscle angiogenesis, and oxidative phosphorylation. A prevalent single nucleotide polymorphism in the MDM2 promoter (SNP309) substitutes a T for a G, supporting a greater transcriptional activity. We aim to assess whether SNP309 impacts intrinsic CRF. METHODS: 82 young healthy nonathletic male and female adults aged 23 ± 2 years performed cardiorespiratory exercise testing to determine their VO₂max (mL kg⁻¹ min⁻¹). The genomic DNAs isolated from saliva were genotyped using Taqman-based qPCR. RESULTS: A one-way ANOVA showed that SNP309 influenced relative VO₂max in the whole cohort (p = 0.044) and in men (p = 0.009), remaining non-significant in women (p = 0.133). VO₂max was higher in TT homozygotes than in GT heterozygotes (whole cohort, 47 ± 12 vs. 42 ± 6 mL kg⁻¹ min⁻¹, p = 0.030; men, 53 ± 8 vs. 45 ± 6 mL kg⁻¹ min⁻¹, p = 0.011). A contingency analysis revealed a positive association between SNP309 in men in which the TT genotype was more frequent in the high VO₂max group (p = 0.006). When considering G as the dominant allele, men bearing a G allele had lower relative VO₂max than TT homozygotes (47 ± 7 vs. 53 ± 8, GG/GT vs. TT, p = 0.010). Conversely, women bearing a G allele had a higher relative VO₂max than TT homozygotes (39 ± 5 vs. 34 ± 7, GG/GT vs. TT, p = 0.047). CONCLUSION: SNP309 impacts VO₂max in a sex-dependent manner in our cohort.