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Long-term voluntary running prevents the onset of symptomatic Friedreich's ataxia in mice.

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.

SUBMITTER: Zhao H

PROVIDER: S-EPMC7142077 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundIn rare disorders diagnosis may be delayed due to limited awareness and unspecific presenting symptoms. Herein, we address the issue of diagnostic delay in Friedreich's Ataxia (FRDA), a genetic disorder usually caused by homozygous GAA-repeat expansions.MethodsSix hundred eleven genetically confirmed FRDA patients were recruited within a multicentric natural history study conducted by the EFACTS (European FRDA Consortium for Translational Studies, ClinicalTrials.gov -Identifier NCT02069509). Age at first symptoms as well as age at first suspicion of FRDA by a physician were collected retrospectively at the baseline visit.ResultsIn 554 of cases (90.7%), disease presented with gait or coordination disturbances. In the others (n = 57, 9.3%), non-neurological features such as scoliosis or cardiomyopathy predated ataxia. Before the discovery of the causal mutation in 1996, median time to diagnosis was 4(IQR = 2-9) years and it improved significantly after the introduction of genetic testing (2(IQR = 1-5) years, p < 0.001). Still, after 1996, time to diagnosis was longer in patients with a) non-neurological presentation (mean 6.7, 95%CI [5.5,7.9] vs 4.5, [4.2,5] years in those with neurological presentation, p = 0.001) as well as in b) patients with late-onset (3(IQR = 1-7) vs 2(IQR = 1-5) years compared to typical onset < 25 years of age, p = 0.03). Age at onset significantly correlated with the length of the shorter GAA repeat (GAA1) in case of neurological onset (r = - 0,6; p < 0,0001), but not in patients with non-neurological presentation (r = - 0,1; p = 0,4). Across 54 siblings' pairs, differences in age at onset did not correlate with differences in GAA-repeat length (r = - 0,14, p = 0,3).ConclusionsIn the genetic era, presentation with non-neurological features or in the adulthood still leads to a significant diagnostic delay in FRDA. Well-known correlations between GAA1 repeat length and disease milestones are not valid in case of atypical presentations or positive family history.

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Long-term voluntary running prevents the onset of symptomatic Friedreich's ataxia in mice.

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