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p62/SQSTM1 and Nrf2 are essential for exercise-mediated enhancement of antioxidant protein expression in oxidative muscle
Journal article   Open access   Peer reviewed

p62/SQSTM1 and Nrf2 are essential for exercise-mediated enhancement of antioxidant protein expression in oxidative muscle

Mami Yamada, Masahiro Iwata, Eiji Warabi, Hisashi Oishi, Vitor A Lira and Mitsuharu Okutsu
The FASEB journal, Vol.33(7), pp.8022-8032
07/2019
DOI: 10.1096/fj.201900133R
PMID: 30913396
url
https://doi.org/10.1096/fj.201900133RView
Published (Version of record) Open Access

Abstract

Increased muscle contractile activity, as observed with regular exercise, prevents oxidative stress-induced muscle wasting, at least partially, by improving the antioxidant defense system. Phosphorylated p62/sequestosome1 competitively binds to the Kelch-like ECH-associated protein 1, activating nuclear factor erythroid 2-related factor 2 (Nrf2), which stimulates transcription of antioxidant/electrophile responsive elements. However, it remains to be determined if this process is activated by regular exercise in skeletal muscle. Here, we demonstrate that muscle contractile activity increases antioxidants, Nrf2 translocation into nuclei, and Nrf2 DNA-binding activity in association with increased p62 phosphorylation (Ser351) in mouse oxidative skeletal muscle. Skeletal muscle-specific loss of Nrf2 [ , Nrf2 muscle-specific knockout (mKO) mice] abolished the expression of the Nrf2 target antioxidant gene NAD(P)H-quinone oxidoreductase 1 (NQO1) in both glycolytic and oxidative muscles but reduced exercise-mediated increases of antioxidants ( , copper/zinc superoxide dismutase (SOD) and extracellular SOD only in oxidative muscle. Interestingly, skeletal muscle-specific loss of p62 ( , p62 mKO mice) also abolished the expression of NQO1 and reduced exercise-mediated increases of the same antioxidants in soleus muscle. Collectively, these findings indicate that p62 and Nrf2 cooperatively regulate the exercise-mediated increase of antioxidants in oxidative muscle.-Yamada, M., Iwata, M., Warabi, E., Oishi, H., Lira, V. A., Okutsu, M. p62/SQSTM1 and Nrf2 are essential for exercise-mediated enhancement of antioxidant protein expression in oxidative muscle.
 Animals Cell Nucleus - enzymology Cells, Cultured Cytoplasm - enzymology Glycolysis Hand Strength Kelch-Like ECH-Associated Protein 1 - biosynthesis Kelch-Like ECH-Associated Protein 1 - genetics Male Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Muscle Contraction - physiology Muscle Fibers, Skeletal - metabolism Muscle, Skeletal - metabolism NF-E2-Related Factor 2 - deficiency NF-E2-Related Factor 2 - genetics NF-E2-Related Factor 2 - physiology Oxidation-Reduction Physical Conditioning, Animal Protein Transport Quadriceps Muscle - metabolism Running Sequestosome-1 Protein - deficiency Sequestosome-1 Protein - genetics Sequestosome-1 Protein - physiology Superoxide Dismutase - biosynthesis Superoxide Dismutase - genetics

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