The common clinical symptoms of Friedreich’s ataxia (FRDA) include ataxia, muscle weakness, type 2 diabetes and heart failure, which are caused by impaired mitochondrial function due to the loss of frataxin (FXN) expression. Endurance exercise is the most powerful intervention for promoting mitochondrial function; however, its impact on FRDA has not been studied. Here we found that mice with genetic knockout and knock-in of the Fxn gene (KIKO mice) developed exercise intolerance, glucose intolerance and moderate cardiac dysfunction at 6 months of age. These abnormalities were associated with impaired mitochondrial respiratory function concurrent with reduced iron regulatory protein 1 (Irp1) expression as well as increased oxidative stress, which were not due to loss of mitochondrial content and antioxidant enzyme expression. Importantly, long-term (4 months) voluntary running in KIKO mice starting at a young age (2 months) completely prevented the functional abnormalities along with restored Irp1 expression, improved mitochondrial function and reduced oxidative stress in skeletal muscle without restoring Fxn expression. We conclude that endurance exercise training prevents symptomatic onset of FRDA in mice associated with improved mitochondrial function and reduced oxidative stress. These preclinical findings may pave the way for clinical studies of the impact of endurance exercise in FRDA patients.

弗里德赖希共济失调 (FRDA) 的常见临床症状包括共济失调、肌肉无力、2 型糖尿病和心力衰竭，这些症状是由于 frataxin (FXN) 表达缺失导致线粒体功能受损所致。耐力运动是促进线粒体功能最有力的干预措施；然而，其对 FRDA 的影响尚未被研究。在这里，我们发现基因敲除和敲入Fxn基因的小鼠（ KIKO小鼠）在 6 个月大时出现运动不耐受、葡萄糖不耐受和中度心脏功能障碍。这些异常与线粒体呼吸功能受损、铁调节蛋白 1 (Irp1) 表达减少以及氧化应激增加有关，而这并非由于线粒体内容物和抗氧化酶表达的损失。重要的是， KIKO小鼠从年轻时（2 个月）开始进行长期（4 个月）自愿跑步完全预防了功能异常，同时恢复了 Irp1 表达、改善了线粒体功能并减少了骨骼肌中的氧化应激，而没有恢复 Fxn 表达。我们得出的结论是，耐力运动训练可以预防小鼠 FRDA 症状的发生，这与改善线粒体功能和减少氧化应激有关。这些临床前发现可能为耐力运动对 FRDA 患者影响的临床研究铺平道路。