Research Grants 23/00380-0 - Biogênese de organelas, Estresse oxidativo - BV FAPESP
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The specific role of PGC-1alpha in skeletal muscle and its interaction with autophagy, mitochondrial biogenesis, oxidative stress and rev-erb-alpha pathways: in vivo and in vitro approaches.

Abstract

The potential benefits of PGC-1 alpha on the mitochondrial function of skeletal muscle are known to be mediated by adaptations induced by physical exercise. However, the interplay of PGC-1alpha with other molecules has not yet been fully elucidated and described in the literature. Therefore, it is essential to unravel the mechanisms by which muscle homeostasis is regulated and which are the key molecules in this control. For this, the main objective of this study is to investigate whether the relationship between PGC-1alpha and Rev-erb-alpha modulates mitochondrial biogenesis, oxidative stress, and autophagy in skeletal muscle. Two independent (in vitro and in vivo) complementary studies are proposed. Study 1: to analyze the effects of manipulation of PGC-1-alpha (Knockdown and overexpression) and Rev-erb-alpha (Knockdown, Knockout and overexpression) in C2C12 cells. Study 2: to investigate the role of physical training on the pathways of mitochondrial biogenesis, autophagy and rev-erb-alpha in the PGC-1alpha muscle-specific knockout mice. At the end of experiments, the following adaptations resulting from physical exercise will be analyzed: functional (physical performance and mitochondrial respiration), morphological (cross-sectional area and proteins involved in the circadian cycle and autophagy), biochemical (antioxidant activity), and molecular (protein content and reactive oxygen species production). Therefore, understanding the role of PGC1alpha and which proteins this transcription factor can modulate is a promising hope for mapping specific pathways responsible for cell survival and muscle health, thus providing new therapeutic and treatment possibilities for disorders involving mitochondrial dysfunction. (AU)

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