Regular and long-term aerobic exercise — in this case, running — slowed the start of Friedreich’s ataxia symptoms and prevented metabolic abnormalities in a mouse model of the disease, researchers report, calling their findings evidence that exercise offers “profound protection” if started at a young age.
The oral presentation, “Voluntary running prevents onset of symptomatic Friedreich’s ataxia in mice,” by Zhen Yan of the Center for Skeletal Muscle Research at the Robert M. Berne Cardiovascular Research Center in Virginia, was part of Thursday’s sessions at the International Ataxia Research Conference (IARC 2017).
The conference continues in Pisa, Italy, through Sept. 30. (A post-session interview with Dr. Yan follows this article.)
“I have been in the muscular exercise research for 30 years and was introduced to Friedreich’s ataxia recently,” Yan said in his presentation. “My lab has a profound interest on the impact of exercise in disease.”
Endurance exercise, also known as aerobic exercise, is a powerful way to stimulate mitochondria, the small organelles in every cell that are responsible for the production of energy and often referred to as the cells’ powerhouses. Exercises such as walking, jogging, swimming, and biking are considered to be aerobic because they increase the breathing and heart rate.
Energy production using oxygen, a process called aerobic respiration, occurs in the cells’ mitochondria.
Friedreich’s ataxia is caused by mutations in the frataxin gene, leading to lower-than-normal levels of the frataxin protein. Frataxin is localized in mitochondria and, at insufficient levels, is known to disrupt its function.
The researchers wondered if endurance exercise might be of benefit to mitochondria and, by extension, to people with Friedreich’s ataxia, whose symptoms can include muscle weakness, type 2 diabetes, and heart failure.
They began by evaluating parameters associated with mitochondria’s function — mitochondrial respiratory proteins and antioxidant enzymes (those involved in preventing the oxidative stress that harm cells) — as well as exercise tests. These included an exercise tolerance test (using a treadmill), and tests of cardiac function (by echocardiogram) and whole body glucose metabolism (glucose tolerance test) in a mouse model of Friedreich’s ataxia (called the KIKO mouse) and in normal, healthy mice.
The tests were performed in the mice at 2, 4 and 6 months of age. Researchers also measured frataxin protein levels at each stage of life, and evaluated the impact of long-term (four months) endurance exercise — voluntary running at a treadwheel.
The diseased mice showed lower frataxin protein level, between 50 and 70 percent below normal, in skeletal muscle (voluntary muscles used in motion), and in heart and liver tissue at all ages compared to healthy mice.
KIKO mice also had poor exercise abilities (exercise intolerance), glucose intolerance — higher than normal blood sugar levels — and a moderate level of cardiac dysfunction at six months old, but not at younger ages.
“We measured cardiac function and we didn’t see much difference, only at 6 months of age” Yan said. “Only when mice reached 6 months of age, they had a significant decrease in running distance.”
According to the researcher, mice at six months are equivalent to 30-year-old people.
These abnormalities were found to be linked to impaired mitochondrial respiratory function, and not lower levels of antioxidant enzymes or mitochondrial respiratory proteins.
“When we subjected [the animals] to the treadmill running, that is the real stress to test them,” Yan said.
“Mouse is a very special species, and they run at night. In this case, they ran every night for about 10 miles,” he added, and for a duration of “about 10 hours” with some rest periods.
Interestingly, four months of voluntary running was seen to prevent cardiac and glucose abnormalities, improve exercise tolerance, and slow the onset of Friedreich’s ataxia symptoms in KIKO mice.
“The glucose intolerance was completely prevented by running,” Yan said, adding “exercise is particularly good at enhancing mitochondria function.”
“Voluntary running as an early life intervention completely mitigates the onset of symptomatic FRDA [Friedreich’s ataxia] in KIKO mice,” Yan said, and this occurs without correcting the defect in frataxin levels.
Yan and his team believe that “exercise can prevent early abnormal pathological features of Friedreich’s ataxia.”
“This is the first study to demonstrate a profound protection of endurance exercise in FRDA in mice, raising exciting possibility of [effective] prevention of FRDA by endurance exercise.” the researchers wrote.
The team is now working on improving exercise models in mice. Weightlifting, for instance, they found improves strength in the animals.
“This is a model that we can use to study the impact of resistance exercise in Friedreich’s ataxia, and thanks to FARA funding we are performing these experiments,” Yan concluded, noting to the Friedreich’s ataxia community: “Stay tunned, we are in the middle of experiments.”
The researchers also plan to further investigate molecular aspects and mitochondrial-related pathways that might be involved in the improvements seen with endurance exercise.
The possibility of conducting similar experiments in humans is being discussed.
Friedreich’s Ataxia News had the opportunity to interview Dr. Yan at IARC 2017.
Yan ended the interview by stating: “I want to emphasize how important research is, and I also want to emphasize the implication of this study … if we can come up with a better and faster, more accurate diagnosis, and with a better understanding of the impact of exercise and the development of the disease, we may be able to find a way to have a huge impact on people who bear this genetic defect.”
The complete interview can be seen below:
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