Sarcopenia is characterized by progressive loss of muscle mass and function associated with age. Invasion of myeloid immune cells (e.g., macrophages) or “inflammaging,” Ca 2+ overload, disruption of neuronal nitric oxide synthase (nNOS) localization at the sarcolemma, and mitochondrial dysfunction are recognized contributors to sarcopenia. However, a central upstream mechanism continues to elude researchers. Ghrelin, or the “hunger hormone”, binds to its ghrelin receptor (GHSR), regulating metabolism, although skeletal muscle has been considered void of GHSR. We recently found that GHSR accumulation in aging tissue leads to insulin resistance and dysfunction. We developed a myeloid cell-specific GHSR knockout (Møghsr-) to test the hypothesis that invading monocytes and macrophages deliver GHSR to skeletal muscle and contribute to the sarcopenic process. Skeletal muscle (gastrocnemius, tibialis anterior, and quadriceps) mass was significantly lower in old (24-month) mice compared with adult (12-month) mice. Møghsr- mice exhibited greater skeletal muscle mass of the gastrocnemius (p = 0.0046), tibialis anterior (p = 0.0056), and quadriceps (p = 0.0293) mass compared with aged wild-type mice. Muscle fiber cross-sectional area was preserved in old Møghsr- mice (p < 0.0001), with fewer small atrophic fibers and a higher proportion of large fibers. GHSR was localized for the first time in muscle cell membrane of old wild-type gastrocnemius muscles but significantly reduced in old Møghsr- mice. Further, old Møghsr- mice exhibited lower myeloid cell invasion (CD68 + ) by ~40%. Myeloid-specific GHSR KO also mitigated aging-associated loss of sarcolemmal nNOS. In addition, calpain activity, a marker of Ca 2 + overload, was reduced by ~50%, while redox defenses (MnSOD) were enhanced. Together, these findings identify that GHSR is delivered to skeletal muscle cells by myeloid immune cells and is causal in the age-associated loss of sarcolemmal nNOS, increased Ca 2+ overload, and sarcopenia as an upstream driver that destabilizes the DGC, disrupts nNOS signaling, and accelerates sarcopenia. Targeting the ghrelin receptor as a novel mechanism for sarcopenia provides a new and important therapeutic pathway. 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.
Othman et al. (Fri,) studied this question.