The role of Nrf2 in exercise training‐mediated regulation of antioxidant enzymes in skeletal muscle

Abstract

Oxidative stress has been implicated in the pathogenesis of skeletal muscle wasting. Regular exercise training prevents oxidative stress‐induced muscle wasting by at least partially improving the antioxidant defense system. However, the underlying molecular mechanisms involved remain elusive. In this study, we assessed whether the nuclear factor erythroid 2‐related factor (Nrf2), the master regulator of antioxidant gene transcription, is essential for the exercise training‐mediated increase in expression of antioxidant enzymes. We performed 3 complementary studies. First, C2C12 myotubes were subjected to 110% cyclic uniaxial stretch for 1 and 6 hours at a frequency of 1 Hz to assess whether stretching regulates mRNA expression of Nrf2. Second, C57BL/6 mice were subjected to either voluntary wheel running for 4 weeks or no exercise to examine whether exercise training regulates Nrf2 and antioxidant enzyme protein expression in muscle. Third, muscle‐specific Nrf2 knockout (Nrf2MKO) and wild‐type littermates (WT) mice were assigned to either exercise training or sedentary groups, and the muscle content of antioxidant enzymes was determined after 4 weeks of exercise training. Our results revealed a significant elevation in Nrf2 mRNA expression in C2C12 myotubes at 6 hours of mechanical stretch. Voluntary running in C57BL/6 mice increased antioxidant enzyme protein (i.e., Cu/ZnSOD, EcSOD) in soleus muscle. Moreover, expression of the Nrf2 target antioxidant gene NQO1 in Nrf2MKO skeletal muscle was abolished compared to WT mice. Loss of Nrf2 in skeletal muscle also blunted the exercise training‐mediated increase in antioxidant enzymes in soleus muscles. These findings indicate that Nrf2 is required for exercise training‐mediated increase of antioxidant enzymes in skeletal muscle.Support or Funding InformationThis study was funded by Grant‐in‐Aid for Challenging Exploratory Research (16K13019) and Grant‐in‐Aid for Scientific Research (B) (15H03080) to M. Okutsu.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.