Investigation of ERK inhibition and Hedgehog signaling in myogenesis and cancer-associated muscle wasting

Abstract

The ability to preserve, protect, or grow skeletal muscle would greatly benefit patients in health and disease. Understanding the molecular pathways that regulate muscle size is necessary to develop interventions. The extracellular signal-related kinase (ERK) and Hedgehog signaling pathways each play necessary roles in skeletal muscle development. The ERK pathway has been shown to both stimulate and inhibit muscle development at different stages, while Hedgehog signaling is vital for embryonic muscle development. Thus, these pathways represent prime targets for manipulation in diseases associated with muscle loss. In prior studies, cancer patients treated with the ERK inhibitor, Selumetinib, experienced significant gains in lean body mass. To study the mechanisms responsible, we tested the potential of Selumetinib to protect against muscle wasting in muscle cell cultures and in mice with experimental lung cancer. Selumetinib was able to induce hypertrophy of cultured muscle cells. In mice, we observed a reduction in tumor mass and in circulating mediators of muscle wasting including inflammatory cytokines. However, Selumetinib treatment did not prevent cancer-induced muscle loss. Together, these data suggest a diversity in the underlying molecular mechanisms and the need for careful consideration when extrapolating results across different disease states, clinical trials, and model systems. In separate studies, we found that the Hedgehog pathway was increased in mice and patients with cancer-associated muscle wasting and inflammation. In a series of studies in muscle cell cultures, in genetically modified mice, and in mice bearing tumors, we found that inflammatory cytokines activated Hedgehog expression in muscle. Hedgehog signaling promoted the replication of muscle stem cells but reduced the expression of genes that specify mature muscle. Inhibiting Hedgehog signaling promoted muscle growth, while activating it caused muscle wasting. Furthermore, we identified unique properties of two proteins activated by Hedgehog, Gli1 and Gli2, where Gli1 appears to promote muscle stem cell proliferation and Gli2 mature muscle gene expression. These data implicate the Hedgehog pathway, GLI1 and GLI2 as targets for treatment of muscle wasting diseases.