NRSA Fellowship for Allison Steele: Analysis of Chronic Muscle Weakness in Post-Septic Mice Using a Novel Resuscitation Protocol

Sepsis is a severe life-threatening condition that damages multiple physiological systems which 1 manifest in a devastating acute critical illness. After discharge from the hospital, 70-100% of severe sepsis 2 survivors report sustained weakness which prevents them from resuming a normal lifestyle. As the mortality 3 rate of sepsis declines due to advancements in critical care medicine and the incidence rate increases due to 4 an aging US population, there are more than 1 million new sepsis survivors every year. It is predicted that the 5 rate of sepsis survivors will continue to rise as the population ages and advancements continue to be made in 6 treatment of sepsis. However, despite recognition of this clinical issue, the molecular mechanisms contributing 7 to chronic muscle dysfunction after sepsis are not well understood due to the lack of an appropriate animal 8 model. Current models are either too mild to induce muscle weakness or are too severe and cause death 9 within a few days. To circumvent this problem, I developed a clinically relevant ICU-like sepsis resuscitation 10 protocol with which 70% of middle-aged mice are rescued from otherwise completely lethal sepsis. The Aims 11 of this project are (1) to test whether the mice that are rescued from lethal sepsis by the ICU-like resuscitation 12 protocol exhibit muscle weakness, and (2) to identify the primary mechanism(s) responsible for muscle 13 weakness after sepsis. Muscle functional analyses will be performed using in vivo and ex vivo strength tests at 14 different time points after sepsis, which will be carefully designed so that the presence of atrophy and/or 15 myopathy can be detected. I have already found that animals with lethal sepsis but rescued using my 16 resuscitation protocol have significant muscle weakness 2 weeks after sepsis induction. Although the 17 mechanisms by which sepsis-induced muscle weakness becomes a chronic condition are unknown, my 18 preliminary data suggest that mitochondrial are involved. Therefore, a series of molecular analyses will be 19 performed to assess the time course and severity of muscle dysfunction and how it may cause reduction in 20 force generating capacity by oxidizing sarcomeric proteins. These studies will promote the development of 21 numerous scientific skill sets including proper animal research design, implementation, and interpretation as 22 well as an assortment of molecular analysis techniques. Successful completion of this project will yield an 23 understanding of the mechanism(s) responsible for muscle weakness after sepsis which could help elucidate a 24 novel therapeutic target to prevent sepsis-mediated from developing in patients.