Endurance exercise prevented the onset of symptoms without the need to restore frataxin production in a mouse model of Friedreich’s ataxia (FA), a study shows, potentially paving the way for clinical research on the impact of endurance exercise in patients.
The study, “Long-term voluntary running prevents the onset of symptomatic Friedreich’s ataxia in mice,” was published in the journal Nature Scientific Reports.
FA is caused by expanded nucleotide repeats in the FXN gene, which provides instructions for the frataxin protein, essential for the function of mitochondria (which generate energy in the cell). Nucleotides are the building blocks of proteins.
Endurance exercise training has been shown to improve mitochondrial function in various tissues in healthy humans and in animals.
However, as a result of having faulty mitochondria — which are particularly relevant in skeletal muscles and the heart — FA patients develop exercise intolerance.
As such, there is a lack of research investigating the impact of exercise on FA patients or animal models, or whether exercise training would reverse or prevent FA development.
Also, if exercise was found to be helpful, when to start training and whether it is beneficial at specific stages of the disease would be important to know.
To answer these questions, researchers at the University of Virginia School of Medicine investigated the impact of endurance exercise in a mouse model of FA.
They used KIKO mice that were genetically engineered to mimic FA by reducing frataxin production in half in the skeletal muscles, heart, and liver, compared to healthy mice.
At 2 and 4 months of age, both KIKO mice and controls were able to run a similar distance and had the same levels of lactate in the blood. However, by 6 months of age, the running distance of KIKO mice was significantly shorter compared to control mice and lactate levels were much higher — a potential indicator of mitochondrial dysfunction.
To test if voluntary endurance running prevented the onset of symptoms, mice were given a running wheel for four months, starting at 2 months of age, which is roughly equivalent to humans at age 7.
After this period, exercise-trained KIKO mice ran over two times farther than KIKO mice that were sedentary. They also ran a greater distance than the healthy mice that did not exercise.
Blood lactate levels in the exercise-trained KIKO mice were significantly lower compared with sedentary KIKO mice. Similar results were found in mice that had two months of training.
Endurance training improved heart function, normalized the levels of two proteins linked to cardiac fibrosis (thickening of the heart muscle) called collagen I and Mmp9, and prevented glucose intolerance in KIKO mice compared to sedentary mice.
To the researchers’ surprise, these improvements were not caused by restored frataxin production, “suggesting that long-term endurance exercise bypasses the need of restoring [frataxin] expression in preventing the pathologies of FRDA [FA],” the scientists wrote. Rather they were due to enhanced mitochondrial function and reduced oxidative stress (oxidative stress occurs due to the buildup of toxic free radicals).
Finally, alterations to key proteins important for mitochondrial function were abolished or prevented by endurance exercise training compared to sedentary KIKO mice.
“We conclude that endurance exercise training prevents symptomatic onset of FRDA in mice associated with improved mitochondrial function and reduced oxidative stress,” the scientists wrote.
“These preclinical findings may pave the way for clinical studies of the impact of endurance exercise in FRDA patients,” they added.
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