Chronic and acute inflammation are significant contributors to skeletal muscle pathology in multiple diseases. Severe inflammation associated with sepsis has profound short- and long-term effects on muscle. Sepsis is characterized by a dysregulated immune response to infection that can alter muscle force generation, wasting, and bioenergetics. Survivors of sepsis have increased risk for the development of persistent acquired weakness syndromes. The inflammatory response in sepsis is mediated by the release of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-?) and interleukin 1 beta (IL-1?). While we know that sepsis-induced changes in skeletal muscle are associated with inflammation, the mechanisms underlying muscle dysfunction in sepsis are not well understood, and there is a significant need to capture the evolution of these impairments to establish effective treatment strategies. Harnessing in vitro models of cytokine-induced myopathy in human skeletal muscle can inform and elucidate fundamental mechanisms of pathology in sepsis enabling development of effective treatments. Resistance training is a widely accepted prescriptive treatment for rebuilding muscle strength and mass. However, post-recovery resistance training has minimal long-term effects in many sepsis patients, and recent studies suggest that early (pre-recovery) physical therapy may preserve muscle fiber cross- sectional area though not strength, indicating a need for further analysis of the complex evolution of sepsis. This evidence formed the cornerstone of our hypothesis that inflammation limits the therapeutic effects of resistance training, which will be tested in a 3D in vitro organoid model through the following specific aims: 1) Establish an in vitro model of sepsis using human SMMT to capture temporal impairments in response to pro-inflammatory agents; 2) Determine recovery of contractile function and structure of engineered SMMT in response to resistance training following exposure to pro-inflammatory agents. The proposed technical innovation and study is important because it will inform the fundamental basis of sepsis-induced myopathies and the potential role of resistance training to ameliorate post-sepsis effects. These results will positively impact future treatment of sepsis and improve the quality of life of post-sepsis survivors.
