Muscle Inflammation is Regulated by NF-kB From Multiple Cells to Muscle Inflammation is Regulated by NF-kB From Multiple Cells to Control Distinct States of Wasting in Cancer Cachexia

Although cancer cachexia is classically characterized as a systemic inflammatory disorder, emerging evidence indicates that weight loss also associates with local tissue inflammation. We queried the regulation of this inflammation and its causality to cachexia by exploring skeletal muscle, whose atrophy strongly associates with poor outcomes. Using multiple mouse models and patient samples, we show that cachectic muscle is marked by enhanced innate immunity. NF-B activity in multiple cells, including satellite cells, myofibers, and fibro-adipogenic progenitors, promotes macrophage expansion derived equally from infiltrating monocytes and resident tissue. Moreover, NF-B activated cells and macrophages undergo crosstalk: whereas NF-B+ cells recruit macrophages to inhibit regeneration and promote atrophy, while interestingly also protecting myofibers, macrophages stimulate NF-B+ cells to sustain inflammation in a feed-forward loop. Together, we propose that NF-B functions in multiple cells in the muscle microenvironment to stimulate macrophage inflammation that both promotes and protects against muscle wasting in cancer.