title: Genetic polymorphisms of the enzymes involved in DNA methylation and synthesis in elite athletes.
abstract: Physical exercise induces adaptive changes leading to a muscle phenotype with enhanced performance. We first investigated whether genetic polymorphisms altering enzymes involved in DNA methylation, probably responsible of DNA methylation deficiency, are present in athletes' DNA. We determined the polymorphic variants C667T/A1298C of 5,10-methylenetetrahydrofolate reductase (MTHFR), A2756G of methionine synthase (MTR), A66G of methionine synthase reductase (MTRR), G742A of betaine:homocysteine methyltransferase (BHMT), and 68-bp ins of cystathionine β-synthase (CBS) genes in 77 athletes and 54 control subjects. The frequency of MTHFR (AC), MTR (AG), and MTRR (AG) heterozygous genotypes was found statistically different in the athletes compared with the control group (P=0.0001, P=0.018, and P=0.0001), suggesting a reduced DNA methylating capacity. We therefore assessed whether DNA hypomethylation might increase the expression of myogenic proteins expressed during early (Myf-5 and MyoD), intermediate (Myf-6), and late-phase (MHC) of myogenesis in a cellular model of hypomethylated or unhypomethylated C2C12 myoblasts. Myogenic proteins are largely induced in hypomethylated cells [fold change (FC)=Myf-5: 1.21, 1.35; MyoD: 0.9, 1.47; Myf-6: 1.39, 1.66; MHC: 1.35, 3.10 in GMA, DMA, respectively] compared with the control groups (FC=Myf-5: 1.0, 1.38; MyoD: 1.0, 1.14; Myf-6: 1.0, 1.44; MHC: 1.0, 2.20 in GM, DM, respectively). Diameters and length of hypomethylated myotubes were greater then their respective controls. Our findings suggest that DNA hypomethylation due to lesser efficiency of polymorphic MTHFR, MS, and MSR enzymes induces the activation of factors determining proliferation and differentiation of myoblasts promoting muscle growth and increase of muscle mass.
authors.affiliation: Division of Metabolic and Cardiovascular Science, San Raffaele Scientific Institute, Milan, Italy. terruzzi.ileana@hsr.it
authors.forename: Ileana
authors.initials: I
authors.lastname: Terruzzi
authors.forename: Pamela
authors.initials: P
authors.lastname: Senesi
authors.forename: Anna
authors.initials: A
authors.lastname: Montesano
authors.forename: Antonio
authors.initials: A
authors.lastname: La Torre
authors.forename: Giampietro
authors.initials: G
authors.lastname: Alberti
authors.forename: Stefano
authors.initials: S
authors.lastname: Benedini
authors.forename: Andrea
authors.initials: A
authors.lastname: Caumo
authors.forename: Isabella
authors.initials: I
authors.lastname: Fermo
authors.forename: Livio
authors.initials: L
authors.lastname: Luzi
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics*; D000328:Adult; D000818:Animals; D056352:Athletes; D016022:Case-Control Studies; D002460:Cell Line; D003541:Cystathionine beta-Synthase / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D005287:Ferredoxin-NADP Reductase / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D051379:Mice; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics*; D055815:Young Adult
chemical_list: C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; D003541:Cystathionine beta-Synthase