FY23 HDSP Learning Collaborative CL1

ABSTRACT The objective of this project is to develop preventive and therapeutic strategies for chronic skeletal muscle weakness in sepsis survivors. Over 1.7 million sepsis survivors are now discharged from US hospitals annually, and a majority of these survivors report reduced quality of life due to considerable muscle weakness years after hospital discharge. The underlying mechanisms for this serious medical issue remained largely unknown as a result of the lack of an animal model that recapitulates the human post-sepsis chronic muscle weakness. Thus, we developed a new murine model that enabled us to identify the specific changes which accompany muscle weakness long after recovery from sepsis. Using this animal model, we demonstrated that sepsis-surviving middle-aged mice exhibit significant skeletal muscle weakness for at least 1 month, long after sepsis symptoms are resolved and muscle mass has recovered. We also showed that this post-sepsis long- term muscle weakness is accompanied by profound structural and functional defects in skeletal muscle mitochondria. We further found that protecting mitochondria in mice, either by genetically overexpressing an antioxidant enzyme or administrating a mitochondria-targeting antioxidant peptide after sepsis induction, can reduce the severity of muscle weakness after sepsis. These results support our hypothesis that mitochondrial damage/dysfunction is the major cause of post-sepsis chronic muscle weakness and that protecting mitochondria during sepsis can prevent the development of this chronic muscle weakness after sepsis. We also hypothesize that existing chronic muscle weakness in sepsis survivors can be ameliorated if damaged mitochondria are replaced by healthy, functional mitochondria. To test these hypotheses, we will pursue the following two specific aims: (1) to evaluate the efficacy of a new resuscitation protocol with mitochondria- targeting antioxidant treatment for preventing post-sepsis muscle weakness, and (2) to formulate mitochondria- targeting therapeutic strategies to ameliorate existing chronic muscle weakness in sepsis survivors. Obtained information will be highly valuable for future treatment of both patients in the ICU and discharged sepsis survivors with chronic muscle weakness.