Genetic ataxia on the move: beyond molecules, the “no pain no gain” formula seems to delay the onset

Friedreich’s ataxia (FRDA) is the most common autosomal recessive ataxia in the Caucasian population with detrimental clinical symptoms, including ataxia, muscle weakness, type 2 diabetes and heart failure. These symptoms usually first appear in childhood or adolescence and worsen over time. A hypertrophic cardiomyopathy is an important clinical trait, which contributes significantly to disability and early death. A high percentage of FRDA patients have glucose intolerance or diabetes mellitus, and exercise capacity is usually severely diminished, leading to wheelchair binding within 10 to 20 years after the disease onset. FRDA is caused by GAA repeat expansions in both alleles of the frataxin (FXN) gene within intron 1 located in chromosome 9 from normally around 5–30 to >90. The GAA expansion mutations lead to reduced expression of frataxin, a mitochondrial protein, which is involved in assembly of iron-sulfur clusters (ISC) and/or function as an iron chaperone or an iron storage protein. This mutation impairs mitochondria, the powerhouses of cells.

Although the precise function of frataxin is not entirely clear yet, substantial evidence shows that frataxin deficiency leads to inefficient use of iron during ISC synthesis, inhibition of ISC formation and/or increased production of oxidative stress. Friedreich’s ataxia affects about 1 in 50,000 people. Symptoms typically appear between ages 5 and 15, though sometimes later; these symptoms include difficulty moving, poor balance, muscle weakness, type 2 diabetes and heart failure. Patients are often confined to a wheelchair within 10 to 20 years of symptom onset. Some patients with advanced disease become completely incapacitated, and the disease can lead to early death. Exercise training is one of the most powerful means for improving mitochondrial function and antioxidant defense in various tissues/organs in healthy humans and animal models. However, whether endurance exercise would be beneficial to FRDA patients is unpredictable as endurance exercise may cause temporary oxidative stress and mitochondrial damage

Ironically, one of the most significant clinical symptoms of FRDA is exercise intolerance, which may be due to the primary defects in the cardiopulmonary and skeletal muscle systems. Now, a top exercise researcher at the University of Virginia School of Medicine is urging clinical trials of exercise in patients with Friedreich’s ataxia after finding that physical activity has a profound protective effect in mouse models of the debilitating genetic disease. Friedreich’s ataxia typically limits patients’ ability to exercise. But the new findings from Zhen Yan, PhD, suggest that well-timed exercise programs early in life may slow the progression of the disease, which robs patients of their ability to walk. The finding could prove particularly important because genetic testing is currently not mandatory, and there are no effective treatments for the condition. In a lab model of the disease, mice lose ability to run, develop blood sugar problems and show signs of moderate heart problems at 6 months of age,

But scientists found that mice that started voluntary long-distance running at 2 months completely avoided those problems. They concluded that endurance exercise training prevents symptomatic onset of Friedreich’s ataxia in mice associated with improved mitochondrial function and reduced oxidative stress. Western blot of oxidated proteins showed increased signal in skeletal muscle sedentary KIKO mice, which was absent in exercise-trained KIKO mice. These findings confirmed that exercise training prevents oxidative stress in FRDA. These preclinical findings may pave the way for clinical studies of the impact of endurance exercise in FRDA patients. The discovery is the latest in a series from Dr. Yan that speaks to the benefits of exercise. He recently made headlines around the world when he determined that exercise may help prevent a potentially deadly complication of COVID-19 known as acute respiratory distress syndrome. Not surprisingly, indeed, scientists have noticed that overweitìght or frankly obese people (i.e. those less physically active) have more chance to catch and develop a more serious form of COVD-19 than leaner people.

Zhen Yan, Director of the Center for Skeletal Muscle Research at UVA’s Robert M. Berne Cardiovascular Research Center, explained: “When dealing with a genetic disease, we often hope that gene therapy is advanced to a point with great precision and efficiency that we can replace the defect gene in the whole genome and in all the affected cells in the body, but the reality is that we are not there yet. This study points to a promising alternative approach of exercise intervention to promote the expression of an iron regulator to bypass the defect gene in maintaining normal mitochondrial function. This could fundamentally change for the good the life of Friedreich’s ataxia patients. Unlike drug therapy, increased physical activity has very few side effects. In fact, regular exercise has positive effects to literally all vital organ systems in our body. You will benefit from just about any type of exercise as you age, as long as you’re not at risk of injury”.

  • Edited by Dr. Gianfrancesco Cormaci, PhD; specialist in Clinical Biochemistry.

Scientific references

Zhao H et al., Yan Z. Sci Rep. 2020 Apr 8; 10(1):6095.

Lynch DR et al. Ann Clin Transl Neurol. 2018; 6(1):15-26.

Bonnechère et al. J Neuroeng Rehabil. 2018; 15(1):87. 

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Informazioni su Dott. Gianfrancesco Cormaci 2450 Articoli
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry specialty in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Detentore di un brevetto sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of a patent concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (leader of the R&D for the partnership CoFood s.r.l.) - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica, salute e benessere sui siti web salutesicilia.com e medicomunicare.it
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