Gly482Ser PGC-1α Gene Polymorphism and Exercise-Related Oxidative Stress in Amyotrophic Lateral Sclerosis Patients

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.

An assessment of treatment guidelines, clinical practices, demographics, and progression of disease among patients with amyotrophic lateral sclerosis in Japan, the United States, and Europe

“…Increased oxidative stress in ALS patients, demonstrated by high level biomarkers for oxidised DNA (6)(7)(8)(9)(10)(11), lipids (10)(11)(12)(13) and proteins (14)(15)(16)(17)(18) or by low level of uric acid (19)(20)(21)(22)(23)(24), has been extensively reported in Asia, the US, and Europe. Increased oxidative stress appears to be a common and underlying phenomenon in ALS, independent of sporadic or familial aetiology (9,16).…”

Exercise-Related Oxidative Stress as Mechanism to Fight Physical Dysfunction in Neuromuscular Disorders

“…It can be speculated that this timeframe is compatible and is required for antioxidant gene transcription activation, the messenger RNA (mRNA) maturation, and its translation into protein, [i.e., superoxide dismutase (SOD), CAT, GPx]. Exercise induces a pleiotropic adaptive response in skeletal muscle, through the activation of transcription factors (e.g., peroxisome proliferator-activated receptor g coactivator 1a, PGC-1a) that regulate mitochondrial biogenesis and activate the transcription of antioxidant enzymes (Pasquinelli et al, 2016). Thus, if the aerobic training is performed for a long time, not only for a limited period (a few weeks), its positive effects on oxidative stress can persist over time, since it keeps the antioxidant enzymatic machinery active.…”

Genetic polymorphisms in amyotrophic lateral sclerosis: Evidence for implication in detoxification pathways of environmental toxicants

“…Gly482Ser SNP has been associated with a decreased gene expression and a reduction in the activity of PCG-1α (Prior et al, 2012). ALS carriers of the Gly482Ser polymorphism show increased exercise-related oxidative stress, despite the lack of strong evidence of association between Gly482Ser and ALS (Pasquinelli et al, 2016). The intracellular redox balance is also influenced from the nuclear factor erythroid-derived 2-like 2 (NFE2L2/Nrf2) pathways.…”