Abstract
The role of exercise in Amyotrophic lateral sclerosis (ALS) pathogenesis is controversial and unclear. Exercise induces a pleiotropic adaptive response in skeletal muscle, largely through the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a transcriptional coactivator that regulates mitochondrial biogenesis and antioxidant defense mechanisms. It has been suggested that a Gly482Ser substitution in PGC-1α has functional relevance in human disorders and in athletic performance. To test this hypothesis, we examined the genotype distribution of PGC-1α Gly482Ser (1444 G > A) in ALS patients to evaluate whether or not the minor serine-encoding allele 482Ser is involved in oxidative stress responses during physical exercise. We genotyped 197 sporadic ALS patients and 197 healthy controls in order to detect differences in allelic frequencies and genotype distribution between the two groups. A total of 74 ALS patients and 65 controls were then comparatively assessed for plasmatic levels of the oxidative stress biomarkers, advanced oxidation protein products, ferric reducing ability and thiol groups. In addition a subgroup of 35 ALS patients were also assessed for total SOD and catalase plasmatic activity. Finally in 28 ALS patients we evaluated the plasmatic curve of the oxidative stress biomarkers and lactate during an incremental exercise test. No significant differences were observed in the genotype distribution and allelic frequency in ALS patients compared to the controls. We found significant increased advanced oxidation protein products (p < 0.001) and significant decreased ferric reducing ability (p < 0.001) and thiol groups (p < 0.001) in ALS patients compared to controls. When comparing different genotypes of PGC-1α, no relation between Gly482Ser polymorphism and oxidative stress biomarker levels was detected in resting conditions. On the other hand, when considering exercise performance, lactate levels were significantly higher (between p < 0.01 and p < 0.001) and greater protein oxidative products were found in AA (Ser482Ser) compared to GG (Gly482Gly) and GA (Gly482Ser) ALS patients. Our findings highlight the importance and confirm the involvement of oxidative stress in ALS pathogenesis. Although not associated with 1444 G > A SNP, ALS patients with Gly482Ser allelic variant show increased exercise-related oxidative stress. This thus highlights the possible role of this antioxidant defense transcriptional coactivator in ALS.
Highlights
Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disorder of motor neurons
In vitro studies support the hypothesis that PGC-1α plays a crucial role in protecting the mitochondria from oxidative stress through the reduced accumulation of reactive oxygen species (ROS) and reduced apoptotic cell death (Valle et al, 2005; St-Pierre et al, 2006)
These data prompted us to evaluate the role of 1444 G > A polymorphism in response to oxidative stress, in basal conditions and during physical activity in sALS patients
Summary
Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disorder of motor neurons. Spinal, and bulbar motor neurons affecting multiple regions of the body leads to progressive motor dysfunction, disability and death. It is clinically characterized by progressive paralysis and eventual death from respiratory failure within 2–5 years (Wijesekera and Leigh, 2009; D’Amico et al, 2013). The distribution of fALS and sporadic cases depends on the ancestral origin of the population, since the frequency of ALS-associated genes, as well as environmental factors vary significantly across different populations (Marin et al, 2015). Oxidative stress biomarkers have been investigated in several studies and show high protein carbonyl levels, increased lipid peroxidation and DNA/RNA oxidative modifications, in the nervous and peripheral tissues in both sporadic and fALS ALS patients (Chang et al, 2008; Barber and Shaw, 2009; Kabuta et al, 2015)
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