Fig 2: Long-term voluntary running promotes Irp1 expression and mitochondrial function in the absence of restored Fxn expression. KIKO mice (2 months of age) were subjected to voluntary wheel running (Ex) (n = 5) or sedentary cage activity (Sed) (n = 4) for 4 months. (A) Representative western blot images and quantification of Fxn protein in gastrocnemius muscle (GA), heart and liver using wild type mice (WT) (n = 4) as control; (B) Oxygen consumption rate (OCR) normalized to mitochondrial protein in isolated mitochondria from GA muscle and heart using Seahorse mitochondrial stress test. Baseline OCR was measured prior to addition of ADP, oligomycin (Oligo) and uncoupler, FCCP; (B) for measurement of maximal capacity and finally addition of antimycin A and rotenone (C) for non-mitochondrial OCR; (C) Representative western blot image and quantification of 4-HNE in gastrocnemius muscle; and (D) Representative western blot images and quantification of Irp1, Tfrc, Ft and Opa1 proteins in gastrocnemius muscle. *P < 0.05 and ***P < 0.001.

Fig 3: Model of ALDH expression and retinol association with FRDA cardiomyopathy. Expression of several enzymes necessary for biosynthesis of RA is altered in FRDA fibroblasts. ALDH1A3 expression is higher in FRDA samples than in age- and sex-matched controls and is especially increased in FRDA samples derived from individuals without a CMP diagnosis. ALDH, aldehyde dehydrogenase; ALDH1A3, aldehyde dehydrogenase family 1 member A3; CMP, cardiomyopathy; FRDA, Friedreich's ataxia; RA, retinoic acid.

Fig 4: Proteins significantly changed in patients with FRDA diagnosed with cardiomyopathy.A, heat map illustrating differentially expressed proteins (p < 0.05) between FRDA CMP+/- groups. B, bar plot of Log2 FC ratios for FRDA CMP+/- groups. C–E, correlation scatter plots displaying AOX1 (C), ALDH1A1 (D), or vimentin (E) protein expression versus age of disease onset for all FRDA samples analyzed by RPPA. Pearson's and Spearman's correlation coefficients (r) were calculated for each comparison. F, correlation scatter plot displaying vimentin protein expression versus FARS score for all FRDA samples analyzed by RPPA. Pearson's and Spearman's correlation coefficients (r) were calculated. G and H, phospho-to-total protein ratios were calculated between FRDA CMP+ and CMP- samples and plotted for p-STAT6 (Y641) and pEGFR (Y1045). Asterisks indicate significant differences: **p < 0.01 and *p < 0.05, using Student's t test. CMP, cardiomyopathy; FARS, Functional Assessment Rating Scale; FC, fold change; FRDA, Friedreich's ataxia; RPPA, reverse phase protein array.

Fig 5: Altered phospho-to-total protein ratios in FRDA fibroblasts.A, heat map displaying expression changes of phosphorylated forms versus total level of proteins that were significantly different (p < 0.05) between FRDA and CTRL samples. B, a summary of the 13 significantly changed phosphoproteins with their calculated Log2 FC in expression and associated p value. CTRL, control; FC, fold change; FRDA, Friedreich's ataxia.