Muscle atrophy is coupled with ferroptosis in the skeletal muscle of Friedreich’s ataxia

Friedreich’s ataxia (FRDA) is a rare genetic disorder caused by an expansion of GAA repeats in the frataxin gene (FXN), resulting in frataxin deficiency. As frataxin is crucial for mitochondrial function by recruiting key iron components such as iron-sulfur clusters and hemes, FRDA is characterized by mitochondrial dysfunction along with abnormal iron metabolism. Recently, ferroptosis, an iron-dependent cell death, has been suggested to play an important role in the development of FRDA, yet if and how ferroptosis impacts FRDA-related muscle weakness has not been studied. Therefore, the objective of this study was to identify the role of ferroptosis in the skeletal muscle of FRDA using whole-body frataxin deficient mice (Fxnnull::YG8s(GAA)>800, #030395, The Jackson Laboratory). FRDA mice (male, 3-months old) had a significantly smaller ratio of muscle mass to body mass, compared to strain-, age-, and sex-matched C57BL/6J control mice, suggesting that this animal model develops muscle atrophy as early as 3 months old upon frataxin deficiency. Furthermore, the FRDA muscles showed elevated non-heme iron levels, which were accompanied by altered iron regulatory protein expressions, including ferritin and ferroportin. In addition, mitochondrial function was decreased in the skeletal muscles of FRDA mice, as evidenced by significantly decreased protein levels of oxidative phosphorylation complexes (OXPHOS I, II, and III; decrease by 31%, 26%, and 15% compared to control, respectively), as well as other mitochondrial capacity markers such as nuclear factor erythroid 2-related factor 1 (Nrf1) and heme oxygenase-1 ( p=0.06). Notably, ferroptosis markers such as Nrf2 and glutathione peroxidase 4 were significantly downregulated in the skeletal muscles of FRDA mice, while apoptotic markers (p53 and caspase 3) were not altered. Collectively, ferroptosis could promote FRDA-related muscle atrophy, which is associated with abnormal mitochondrial iron status and function. Our results also suggest that ferroptosis may represent a novel target for correcting or ameliorating the development and progression of muscle atrophy in FRDA patients. Future studies are warranted to determine the molecular mechanism of ferroptosis in FRDA-related mitochondrial dysfunction and to develop therapeutic strategies for muscle weakness in FRDA or other types of ataxias. This study was supported in part by the NIH NS121394 and UMass Lowell Internal Seed Grant. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.