Abstract
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.
Highlights
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
We confirmed that KIKO mice have reduced frataxin protein expression at ~50% of the levels in wild type control mice (WT) mice in skeletal muscle, heart and liver at www.nature.com/scientificreports
The major findings of this study include: (1) KIKO mice had an age-dependent development of exercise intolerance, cardiac dysfunction and metabolic abnormality; (2) Young KIKO mice had normal functional adaptations in response to 4 weeks of endurance exercise training, including improved exercise capacity, glucose metabolism and cardiac function; (3) Long-term voluntary running starting early in life prevented symptomatic onset of FRDA in KIKO mice, raising the possibility of using endurance exercise training to prevent the onset of FRDA in early diagnosed patients; and (4) Long-term voluntary running improved mitochondrial function in skeletal muscle and heart in the absence of restored Fxn expression, but with evidence of restored expression of Irp[1] as well as reduced oxidative stress in skeletal muscle
Summary
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. 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. We subjected KIKO mice to long-term voluntary running and investigated the impact of endurance exercise and dissected the potential mechanisms that might underlie the impacts of exercise
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