Muscle‐specific Nrf2 deficiency exacerbates cancer cachexia‐induced skeletal muscle atrophy

Abstract

Skeletal muscle atrophy is a hallmark of several debilitating diseases such as cancer, thereby contributing to morbidity and mortality. Oxidative stress, which is caused by excessive production of reactive oxygen species and/or decreased antioxidant defense, 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. To investigate this, C57BL/6 mice were given a subcutaneous injection in the left flank with 107 3LL lung cancer cells or PBS control. A grip strength test was performed at 25–27 days after 3LL injection using a grip strength meter. At 4 weeks after 3LL injection, soleus, plantaris, gastrocnemius, and extensor digitorum longus muscles were harvested to assess muscle weight and expression of select proteins. Muscle‐specific Nrf2 knockout (Nrf2mKO) and wild‐type littermates (WT) mice were also injected with 3LL cells and their skeletal muscles were harvested within the same time frame. Our results demonstrated that grip strength in 3LL injected C57BL/6 mice was significantly lower than in control mice. Gastrocnemius and extensor digitorum longus muscle weights in 3LL injected mice were significantly lower than control mice. Protein carbonylation, a surrogate of oxidative stress, was significantly increased in 3LL injected mice compared with control mice. Extracellular superoxide dismutase (EcSOD) protein expression was also increased in 3LL injected mice. Gastrocnemius and extensor digitorum longus muscle weight in 3LL injected Nrf2mKO mice were significantly lower than in 3LL injected WT mice. Loss of Nrf2 in skeletal muscle also blunted the 3LL injection‐induced increase in EcSOD protein expression. These findings indicate that endogenous muscle Nrf2 is a key protective molecule against atrophy likely by limiting the oxidative stress burden of cancer cachexia.Support or Funding InformationThis study was funded by Grant‐in‐Aid for Scientific Research (B) (15H03080) (18H03153) to Mitsuharu Okutsu.