PROJECT SUMMARY Sepsis is a condition of life-threatening organ dysfunction caused by a dysregulated host response to infection and carries a high risk of mortality, especially among older adults. Despite decreasing in-hospital mortality due to early recognition and aggressive intensive care unit (ICU) management, a rapidly growing number of “sepsis survivors” experience persistent and severe skeletal muscle weakness and atrophy (i.e. sepsis-induced myopathy). These patients often experience prolonged periods of bed rest, which possibly worsens the myopathy. For unknown reasons, the skeletal muscles of these patients never return to their pre-septic functional condition. Healthy skeletal muscles possess a great regenerative capacity that is regulated by a populations of resident cells known as satellite cells (SCs). SCs are localized between the muscle membrane and the basal lamina and are exposed to other cells and their secretory products, including chemokines, in the so called SC niche. We have shown that SCs lose their ability to regenerate muscle fibers in sepsis, a response that is known to occur in the process of aging. We have also shown that sepsis induces epigenetic changes in the SCs that are associated with the loss of function. Our preliminary observations identified circulatory chemokines known to be elevated in sepsis and aging. Exposure of healthy SCs to this septic serum resulted in a loss of myogenic capacity. The mechanisms by which the combination of sepsis, aging and skeletal muscle disuse contributes to the persistent myopathy and failure to regenerate in older adults remain unknown. We will test the overarching hypothesis that when faced with severe immunological stress of sepsis, on top of aging and disuse, these critically important resident cells are unable to facilitate complete recovery of muscle function. We will test this hypothesis with two specific aims. Drawing largely from clinical observations and our unpublished preliminary data we will combine a classic model of sepsis with hindlimb suspension followed by reloading to 1) test the hypothesis that disuse aggravates skeletal muscle dysfunction and hampers repair via satellite cell dysfunction in aged septic hosts; and 2) determine the epigenetic signatures of satellite cells from aged septic hosts and the role of chemokine receptors on these signatures. We anticipate that this study will result in a novel pre-clinical model to study sepsis-induced myopathy in aging. The identification of epigenetic signatures in SCs of aged septic hosts will reveal therapeutic targets for epigenetic modifiers to attenuate the myopathy. In due course, this can benefit a substantial number of older adults who have worsened muscle function after admission to the ICU and may be applicable for older patients who are exposed to other types of infections, such as those affected by the current COVID-19 pandemic.