Friedreich’s ataxia (FA) is an inherited disorder caused by deficiency of the mitochondrial protein frataxin (FXN). Cardiomyopathy is a leading cause of mortality in FA, but mechanisms linking FXN loss to autonomic nervous system (ANS) dysfunction and heart failure remain unclear. We used a muscle-specific FXN knockout (FXN-cKO) mouse model that recapitulates severe cardiac abnormalities seen in FA patients. Cardiac sympathetic activity and signaling were assessed by expression of monoamine oxidase A (MAO-A) and tyrosine hydroxylase, FRET biosensor analysis of β1-adrenergic receptor (β1AR) signaling at the sarcoplasmic reticulum (SR) versus plasma membrane (PM), calcium transients, electrocardiography, and echocardiography. Oxidative damage was quantified by 4-hydroxynonenal (4-HNE). Therapeutic testing included the MAO-A inhibitor clorgyline, the Nrf2 activator omaveloxolone (OMAV), or both. Parallel studies were performed in FA patient-derived fibroblasts differentiated into myofibroblasts. FXN-cKO hearts showed increased MAO-A and tyrosine hydroxylase, indicating elevated sympathetic drive. SR-specific β1AR signaling was impaired despite preserved PM signaling, disrupting calcium handling and predisposing to arrhythmia. Clorgyline restored SR signaling, reduced 4-HNE, lowered circulating norepinephrine, and partially improved conduction by shortening QRS intervals. Clorgyline alone did not restore J-waves in mice, a marker of early repolarization, but dual therapy with clorgyline and OMAV rescued J-waves and improved echocardiographic measures of function, largely driven by OMAV. In human FA fibroblasts under oxidative stress, OMAV and dual treatment with clorgyline strongly protected cell survival, while clorgyline alone improved survival only modestly. These findings identify SR-localized sympathetic signaling defects as a novel mechanism for arrhythmia in FA hearts. Dual targeting of MAO-A and Nrf2 provides complementary benefits, with clorgyline improving ANS and OMAV driving antioxidant defense, altogether restoring cardiac conduction and function.
Figueroa et al. (Sun,) studied this question.