(LB03-04-25) Metabolic Reprogramming in Septic Mice With High-Protein Diet and Exercise

Objectives: Sepsis represents 20% of deaths worldwide, and the survivors have a greater risk of death within 5 years. Infection-driven reprogramming of metabolism by infection causes organ dysfunction and poor outcomes. However, little is known about metabolic interventions aimed to improve outcomes. High-protein diet combined with exercise may be a promising intervention to improve recovery from sepsis. The hypothesis of this work is that high-protein diet combined with exercise will protect mice from outcomes of sepsis due to increase in muscle mass. We aim to define the physiologic and metabolic impact of combined prophylactic high-protein diet and physical activity on sepsis outcomes.

Methods: To test the hypothesis, 8 week old C57BL male mice were exposed to high-protein diet (HP) or chow diet (CT) with or without access to running wheels (SED or EXE) during 4 weeks before being subjected to the gold standard model of polymicrobial sepsis (cecal ligation and puncture).

Results: Our data showed that mice fed with HP diet for 4 weeks before sepsis had a better probability of survival (66.66%) compared to mice fed with chow (CT) diet (42.85%) in the polymicrobial model. In this same experiment, when exercise was added, HP+EXE mice had even better survival (87.50%) compared to CT-EXE (50%). In addition, HP+EXE mice recovered faster than CT-EXE post-sepsis which is measurable by a greater number of laps in the running wheels 120h post-sepsis. The improved mortality may be due to increased lean mass in the HP+EXE group compared to CT-SED since week 1 of exercise until week 4. Metabolic cage revealed increased in VO₂ and energy expenditure in HP+SED compared to CT-SED in the first week exposed to HP. The respiratory change ratio was 1 in the chow group compared to 0.92 in the HP group, representing increase in protein/fat as energy source. Further, HP+SED group demonstrated markedly faster recovery as indicated by increased activity counts compared to CT-SED. Our next steps are exploring the mechanism behind the survival through the HP diet.

Conclusions: High-protein diet combined with voluntary exercise for 4 weeks before sepsis increased lean mass and improved survival in mice. High-protein diet alone increased VO₂ and energy expenditure, and accelerated recovery. These data offer important insight to the prevention and treatment of sepsis.

Funding Sources: Yale University startup package