Muscle contractile activity‐mediated regulation of antioxidant enzymes in oxidative muscle requires p62/SQSTM1 phosphorylation‐induced Nrf2 activation

Abstract

Enhanced muscle contractile activity, as observed with regular exercise, prevents oxidative stress‐induced muscle wasting, at least partially by improving the antioxidant defense system. p62/sequestosome1 (p62/SQSTM1) competitively binds to the kelch‐like ECH‐associated protein 1, activating nuclear factor erythroid 2‐related factor 2 (Nrf2), which stimulates transcription of genes containing 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 increased muscle contractile activity enhances antioxidant enzyme expression, Nrf2 translocation into nuclei, and Nrf2 DNA‐binding activity in mouse skeletal muscle. Basal skeletal muscle expression of the Nrf2 target antioxidant gene NAD(P)H‐quinone oxidoreductase 1 (NQO1) is markedly reduced in muscle‐specific Nrf2 knockout (Nrf2 mKO) mice and muscle‐specific p62 knockout (p62 mKO) mice when compared to wild type littermates (WT). Using voluntary running, we demonstrate that regular endurance exercise increases levels of total p62 and Ser 351 phosphorylation of p62, an event that enhances p62 affinity to Keap1, in the oxidative soleus muscle. Regular exercise fails to increase the expression of the antioxidant proteins CuZnSOD (i.e., SOD1) and EcSOD (i.e., SOD3) in the soleus of Nrf2 mKO and p62 mKO. However, the exercise‐mediated elevation of these proteins is preserved in glycolytic skeletal muscle of Nrf2 mKO and p62 mKO mice. Collectively, these findings indicate that p62 and Nrf2 cooperatively regulate the exercise‐mediated increase of antioxidant enzyme expression in oxidative muscle, and that an alternate molecular regulation of these genes predominates in glycolytic muscle fibers in response to regular exercise.Support or Funding InformationThis study was supported by Grant‐in‐Aid for Research Activity start‐up (25882036), Grant‐in‐Aid for Scientific Research (B) (15H03080), Grant‐in‐Aid for Scientific Research (B)(18H03153), Suzuken Memorial Foundation, Toyoaki Scholarship Foundation, The Nakatomi Foundation, and The Uehara Memorial Foundation to Mitsuharu Okutsu.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.