Invasion of the Ghrelin Receptor in Cachectic Skeletal Muscle with Colon Cancer

Cachexia is a syndrome characterized by over a 10% loss in body mass and skeletal muscle wasting, usually linked to an underlying illness. The prevalence of cachexia with colon cancer is high, tallying close to 50% of patients. The mechanisms leading to skeletal muscle wasting are multifactorial and complex, with particular attention paid to inflammatory signaling. The growth hormone receptor-1a (GHSR) is a G-protein coupled receptor for the “hunger hormone” ghrelin and while present in the brain, lungs, liver, etc. is believed to be absent in skeletal muscle. While GHSR or “ghrelin receptor” regulates glucose metabolism and metabolism, GHSR contributes to inflammaging and sarcopenia in part though novel infiltration in aging skeletal muscle (Othman APS, 2026). Furthermore, ablation of GHSR mitigated the loss of neuronal nitric oxide synthase (nNOS) at the muscle cell membrane, critical for maintaining skeletal muscle mass and metabolism. We hypothesized that skeletal muscle in mice with genetically spontaneous colon tumors would experience infiltration of GHSR and a loss of nNOS localization at the muscle cell membrane. Gastrocnemius muscle cross-sectional area (CSA) was significantly lower (-30%) in colon tumor mice vs. control mice. Further, there was 3.5X greater levels of GHSR+ staining in the gastrocnemius muscles of the tumor grow vs. health controls. GHSR positive staining was primarily localized at the skeletal muscle cell membrane. However, some of the smaller muscle fibers also displayed internal localization of GHSR. Furthermore, there was a profound reduction of sarcolemmal nNOS in the tumor-bearing mice vs. controls. In summary, we report two novel observations of cachectic muscles in tumor-bearing mice: (1) invasion of the ghrelin receptor to the sarcolemma and internal trafficking of GHSR into a portion of small fibers, and (2) substantial loss of nNOS in cachectic muscle consistent with our hypothesis. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.