Antioxidant treatment improves in vivo cardiac and skeletal muscle bioenergetics in patients with Friedreich's ataxia

Abstract

Friedreich's ataxia (FA) is the most common form of autosomal recessive spinocerebellar ataxia and is often associated with a cardiomyopathy. The disease is caused by an expanded intronic GAA repeat, which results in deficiency of a mitochondrial protein called frataxin. In the yeast YFH1 knockout model of the disease there is evidence that frataxin deficiency leads to a severe defect of mitochondrial respiration, intramitochondrial iron accumulation, and associated production of oxygen free radicals. Recently, the analysis of FA cardiac and skeletal muscle samples and in vivo phosphorus magnetic resonance spectroscopy (31P-MRS) has confirmed the deficits of respiratory chain complexes in these tissues. The role of oxidative stress in FA is further supported by the accumulation of iron and decreased aconitase activities in cardiac muscle. We used 31P-MRS to evaluate the effect of 6 months of antioxidant treatment (Coenzyme Q10 400 mg/day, vitamin E 2,100 IU/day) on cardiac and calf muscle energy metabolism in 10 FA patients. After only 3 months of treatment, the cardiac phosphocreatine to ATP ratio showed a mean relative increase to 178% (p = 0.03) and the maximum rate of skeletal muscle mitochondrial ATP production increased to 139% (p = 0.01) of their respective baseline values in the FA patients. These improvements, greater in prehypertrophic hearts and in the muscle of patients with longer GAA repeats, were sustained after 6 months of therapy. The neurological and echocardiographic evaluations did not show any consistent benefits of the therapy after 6 months. This study demonstrates partial reversal of a surrogate biochemical marker in FA with antioxidant therapy and supports the evaluation of such therapy as a disease-modifying strategy in this neurodegenerative disorder.

Mitochondrial Dysfunction as a Therapeutic Target in Progressive Supranuclear Palsy

“…Significant differences were detected for the scales most specific for PSP, namely the PSP rating scale (Golbe 1997) and the frontal assessment battery (Dubois et al 2000). Our findings are in line with previous trials demonstrating that coenzyme Q10 ameliorates clinical symptoms in diverse diseases, which are all characterized by mitochondrial dysfunction, such as myopathies, Friedrich's ataxia, or Parkinson's disease (Bresolin et al 1988;Lodi et al 2001;Shults et al 2002). Since it is unlikely that the 6-week treatment has induced regenerative processes, it may rather be that a restoration of higher energy levels may have led to a restoration of lost functions in individual neurons, thereby leading to mild clinical improvement.…”

Mitochondrial Dysfunction in Neurodegenerative Diseases

“…We have assessed the efficacy of long term treatment of 10 patients with FRDA with high doses of vitamin E (2100 IU/day) and coenzyme Q10 (400 mg/day). After 6 months 31 P MRS data indicated that heart and skeletal muscle energetics were significantly improved [62]. Four year follow up data from this study showed the enhanced energy levels were maintained, clinical parameters were stabilised or improved in 7 out of 10 patients and heart fraction shortening had improved [63].…”

Cellular Stress Response: A Novel Target for Chemoprevention and Nutritional Neuroprotection in Aging, Neurodegenerative Disorders and Longevity

“…FRDA patients have been treated with a variety of antioxidants including idebenone and vitamin E [231]. Lodi et al [232], using in vivo phosphorus magnetic resonance spectroscopy (31P-MRS), showed that after only 3 months of treatment with coenzyme Q10 and vitamin E (Coenzyme Q10 400 mg/day, vitamin E 2100 IU/day), the cardiac phosphocreatine to ATP ratio increased to 178% (P = 0.03) and the maximum rate of skeletal muscle mitochondrial ATP production increased to 139% (P = 0.01) of their respective baseline values in the FRDA patients. These improvements were sustained after 6 months of therapy.…”