TESTOSTERONE INDUCES UP-REGULATION OF MITOCHONDRIAL GENE EXPRESSION IN SKELETAL MUSCLE CELLS ACCOMPANIED BY AN INCREASE OF NUCLEAR RESPIRATORY FACTOR-1 AND ITS DOWNSTREAM EFFECTORS

PRONSATO, LUCÍA; FRATTINI, NATALIA; MILANESI, LORENA; VASCONSUELO, ANDREA

Mar del Plata

Congreso; LXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2019

SAIC

The loss of muscle mass and strength with aging, sarcopenia, is a prevalent condition among the elderly, associated with skeletal muscle dysfunction and enhanced muscle cell apoptosis and mitochondrial dysfunction. We have previously demonstrated that testosterone (T) protects against H2O2-induced apoptosis in C2C12 muscle cells, at different levels: morphological, biochemical and molecular. However, the role of T and its receptor at mitochondrial level is not well understood. Therefore, here we investigated the impact of physiological concentration of T on mitochondrial gene expression in C2C12 skeletal muscle cells. We found that T caused a significant increase in mRNA expression of genes encoded by mitochondrial DNA, namely NADPH dehydrogenase subunit 1 (ND1), subunit 4 (ND4), cytochrome b (CytB), and cytochrome c oxidase subunit 1 (Cox1) and subunit 2 (Cox2) in skeletal muscle cells. In addition, gene and protein expression of the nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factors A (Tfam) and B2 (TFB2M), key regulators of mitochondrial transcription and biogenesis, were also increased after T treatment. Of relevance, the simultaneous treatment with T and the androgen receptor antagonist, Flutamide, reduced these effects. The actions of the hormone observed were totally opposite to H2O2-oxidative stress induced treatment, which significantly reduced mitochondrial gene expression. Computational analysis revealed that mitochondrial DNA contains specific sequences, which the androgen receptor could recognize and bind, probably taking place thus, a direct regulation of mitochondrial transcription by the receptor. These findings indicate that androgen plays an important role in mitochondrial gene expression and biogenesis in skeletal muscle.