Abstract Body: Background: Friedreich's ataxia (FA) is a progressive neurodegenerative disorder. FA is caused by a deficiency in the frataxin protein due to an expansion of GAA repeats in the first intron of the frataxin gene. Reduced frataxin protein expression is thought to negatively affect mitochondrial function, leading to increased oxidative damage. Although FA is considered a neurodegenerative disorder, it is not completely understood why most patients present with left ventricular systolic dysfunction and die from cardiac events.
Objective: The objective of our study is to determine whether abnormal calcium handling is a molecular mechanism of cardiac dysfunction in FA.
Methods: We used the frataxin knock-out (KO) mouse model of FA as well as human heart samples from donors with FA and from unaffected donors. The expression of calcium-handling proteins was assessed using proteomics and westernblot. We used echocardiography and telemetric ECG to assess cardiac function in the mice. We also performed in-vivo programmed electrical stimulation (PES) to assess ventricular arrhythmogenesis in the mouse heart.
Results: Proteomics and western blot showed that SERCA2, Ryr2, PLN, CASQ2, and CaMKII were downregulated and that the phosphorylation of Ryr2 and PLN (Ser16 and Thr17) were also significantly decreased in left ventricular tissue from humans with FA and from KO mice. The mitochondrial calcium handling proteins VDAC and MCU were upregulated in left ventricular tissue from humans with FA and from KO mice. On telemetric ECG, the RR tended to prolong in the KO animals compared to wild types (p=0.053), and heart rate variability analysis indicated heightened cardiac parasympathetic input. Echocardiography showed that the ejection fraction and fractional shortening were significantly decreased and left ventricular wall thickness and diameter were significantly increased in the KO mice. In PES, ventricular arrhythmogenesis was greater in KO mice compared to wild types.
Conclusions: The reduced expression of calcium handling proteins may contribute to cardiac contractile and electrophysiological abnormalities in FA.

Keywords: Friedreich's ataxia, SERCA2, Ryr2, PLN, CASQ2, and CaMKII.