Figure 7

Bezafibrate rescues mitochondrial bioenergetics and prevents left ventricle cardiac hypertrophy in Costello syndrome. (A) Increased expression of PGC1α, TFAM, and p-P70S6K by bezafibrate (500 μM; 48 hours) treatment in skin fibroblasts from patients with CS. (B) CLPX protein content determined by mass spectrometry of cells from controls, cells from patients with CS, and bezafibrate-treated cells from patients with CS. Quantification was expressed as the normalized peak intensity (n = 3). (C–F) Defective mitochondrial respiration, OXPHOS coupling, mitochondrial transmembrane electric potential, and mitochondrial ATP levels were rescued by bezafibrate (500 μM; 48 hours) in skin fibroblasts from patients with CS (n = 3). (G) Stimulation of respiratory chain complex enzymatic activity in the hearts of CS mice treated with bezafibrate 0.05% in the diet (for 12 weeks). Effect of the bezafibrate 0.05% in chow diet (CD + BZ 0.05%) on (H) left ventricle (LV) mass, (I) left ventricle volume, (J) heart mass, (K) heart beating rate, and (L) systolic arterial pressure after 12 weeks of treatment in CS mouse model (n = 9) as compared with untreated CS mice fed with chow diet (CD) (n = 9). One-way ANOVA with Dunnett’s correction for multiple testing was used to compare the 4 groups of cells (controls treated or untreated with bezafibrate and CS mice treated or untreated with bezafibrate). Unpaired t test was used to compare the 2 groups of mice (WT or Costello). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.