Cancer cachexia‐mediated regulation of EcSOD synthesis requires Nrf2 activation by p62 phosphorylation

Abstract

Oxidative stress plays an important role in skeletal muscle atrophy in cancer cachexia. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator of antioxidant gene transcription. However, a potential role for Nrf2 in protection against muscle atrophy in cancer cachexia remains to be determined. Here, we demonstrated that Lewis lung carcinoma (LLC) cells injection in subcutaneous of C57BL/6 mice induces severe muscle atrophy in glycolytic muscle, as well as oxidative marker (i.e., malondialdehyde proteins) and atrogenes (i.e., atrogin-1 and MuRF1). Basal level of antioxidants expression in glycolytic extensor digitorum longus muscle was lower than in oxidative soleus muscle. LLC injection increased extracellular superoxide dismutase (EcSOD) protein expression in association with Nrf2 activation in extensor digitorum longus muscles. Muscle-specific loss of Nrf2 [i.e., Nrf2 muscle-specific knockout (mKO) mice] induced more severe muscle atrophy by cachexia in extensor digitorum longus muscle than in soleus muscle. LLC injection-mediated enhanced EcSOD protein expression in extensor digitorum longus muscle was blunted in Nrf2 mKO mice. Interestingly, LLC injection-induced p62 phosphorylation enhanced EcSOD protein expression in extensor digitorum longus muscle was blunted in p62 mKO mice. Collectively, these findings indicate that muscle Nrf2 activation by p62 phosphorylation plays an important for antioxidant defense system in skeletal muscle and protect against cachexia-induced muscle atrophy.