Nrf2 contributes to the benefits of exercise interventions on age-related skeletal muscle disorder via regulating Drp1 stability and mitochondrial fission

Abstract The progressive and generalized loss of skeletal muscle mass and function, also known as sarcopenia, underlies disability, increasing adverse outcomes and poor quality of life in older people. Exercise interventions are commonly recommended as the primary treatment for sarcopenia. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a vital role in regulating metabolism, mitochondrial function, and the ROS-dependent adaptations of skeletal muscle, as the response to exercise. To investigate the contribution of Nrf2 to the benefits of exercise interventions in older age, aged (∼22 month old) Nrf2 knockout (Nrf2-KO) mice and age-matched wild-type (WT) C57Bl6/J mice were randomly divided into 2 groups (sedentary or exercise group). We found that exercise interventions improved skeletal muscle function and restored the sarcopenia-like phenotype in WT mice, accompanied with the increasing mRNA level of Nrf2. While these alternations were minimal in Nrf2-KO mice after exercise. Further studies indicated that Nrf2 could increase the stability of Drp1 through deubiquitinating and promote Drp1-dependent mitochondrial fission to attenuate mitochondrial disorder. We also observed the effects of sulforaphane (SFN), a Nrf2 activator, in restoring mitochondrial function in senescent C2C12 cells and improving sarcopenia in older WT mice, which were abolished by Nrf2 deficiency. These results indicated that some benefits of exercise intervention to skeletal muscle were Nrf2 mediated, and a future work should focus on Nrf2 signaling to identify a pharmacological treatment for sarcopenia.