Fasting Drives Nrf2-Related Antioxidant Response in Skeletal Muscle.

Daniele Lettieri-Barbato,Rocco Caggiano,Giuseppina Minopoli,Raffaella Faraonio,Rossella Izzo,Katia Aquilano,Mariarosaria Santillo

doi:10.3390/ijms21207780

Abstract

A common metabolic condition for living organisms is starvation/fasting, a state that could play systemic-beneficial roles. Complex adaptive responses are activated during fasting to help the organism to maintain energy homeostasis and avoid nutrient stress. Metabolic rearrangements during fasting cause mild oxidative stress in skeletal muscle. The nuclear factor erythroid 2-related factor 2 (Nrf2) controls adaptive responses and remains the major regulator of quenching mechanisms underlying different types of stress. Here, we demonstrate a positive role of fasting as a protective mechanism against oxidative stress in skeletal muscle. In particular, by using in vivo and in vitro models of fasting, we found that typical Nrf2-dependent genes, including those controlling iron (e.g., Ho-1) and glutathione (GSH) metabolism (e.g., Gcl, Gsr) are induced along with increased levels of the glutathione peroxidase 4 (Gpx4), a GSH-dependent antioxidant enzyme. These events are associated with a significant reduction in malondialdehyde, a well-known by-product of lipid peroxidation. Our results suggest that fasting could be a valuable approach to boost the adaptive anti-oxidant responses in skeletal muscle.

Highlights

Metabolic adaptation responses are essential to preserve energy homeostasis for basic functions in the organism during fasting
Since fasting signaling could lead to mild oxidative stress, in this paper we explored nuclear factor erythroid 2-related factor 2 (Nrf2) signaling in skeletal muscle and gave evidence that metabolic reprograming during fasting occurs in parallel with a protective response, resulting in the boosting of antioxidant defense and protection against lipid peroxidation
We found the induction of some Nrf2-target genes, including those involved in GSH biosynthesis and recycling, as well as in heme metabolism, like Ho-1, the master regulator of heme level, and others implicated in mitochondrial performance and reactive oxygen species (ROS) scavenging, like Ucp3 and Cat, respectively

Summary

Introduction

Metabolic adaptation responses are essential to preserve energy homeostasis for basic functions in the organism during fasting. Molecular mechanisms controlling nutrient-induced metabolic reprogramming involve an intricate system of inducers and effectors that primarily boost adaptive metabolic responses and increase stress resistance to ensure tissue homeostasis and eventually prevent cells from death commitment [2,7,16,17,18,19]. Activation of the Nrf pathway occurs under the influence of a wide variety of intrinsic or extrinsic stresses that include byproducts of metabolic processes (e.g., ROS), exposure to chemical/environmental agents and conditions of nutrient disturbances (e.g., fasting, overfeeding) [25,29,30,31,32,33,34]. The role of Nrf in skeletal muscle under nutrient stress conditions remains under-investigated

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Conclusion