Thursday, November 21, 2024
11/21/2024
ABSTRACT Sepsis is a potentially life-threatening complication of an infection in critically ill patients and is characterized by severe tissue breakdown, leading to long-term muscle weakness, fatigue, and reduced physical activity. Early and targeted nutritional intervention is critical in enhancing rehabilitation from critical illness. The continuing high morbidity and mortality rate in sepsis illustrates the clinical and scientific need to dissect the underlying mechanisms by which sepsis induces accelerated catabolic response in muscle, and to assess the effectiveness of targeted nutritional approaches during rehabilitation from sepsis. The rationale is that the mechanistic insights generated will lay the foundation for the development of novel nutritional approaches for critically ill patients to enhance rehabilitation through improved muscle health and physical activity. The use of translational animal models is essential. Therapeutic nutritional support in pig models is viewed as highly translational to humans. Our pig sepsis rehabilitation model shows many characteristics of human sepsis rehabilitation like reduced muscle protein synthesis and increased protein breakdown, muscle weakness, reduced activity and lower muscle autophagy. The first aim of the proposed study is to test the hypothesis that a targeted, combined nutritional formulation of β-hydroxy β-methylbutyric acid (HMB anti-catabolic) and essential amino acids (EAA, anabolic) is superior to EAA alone or control in attenuating severe tissue breakdown during rehabilitation from sepsis. The hypothesis is that the EAA+HMB combination will simultaneously increase muscle protein synthesis, attenuate muscle catabolism and wasting, and improve the rehabilitation of muscle function, leading to enhanced physical activity. The second aim is to identify the metabolic and molecular mechanisms through which supplementation attenuates the dysregulated proteostasis that causes the severe protein breakdown. The proposed specific aims will be studied in our clinically relevant pig model of rehabilitation from an acute Pseudomonas aeruginosa sepsis. The nutritional intervention will be studied using a randomized, controlled, double-blind 3 arm design (EAA+HMB vs. EAA vs. control). The proposed study is innovative because a) the targeted novel approach of EAA+HMB nutritional supplementation to attenuate tissue breakdown and restore muscle function and functional outcome (strength, fatigue and physical activity) and b) mechanistic insights into sepsis-induced severe tissue breakdown and recovery. The use of an innovative stable tracer methodology with muscle and plasma sampling will enable the quantification of all metabolic fluxes and molecular endpoints. The results of the proposed study will have a positive impact by providing a mechanistic basis for the development of novel, cost-effective nutritional approaches for patients recovering from sepsis that will enhance their rehabilitation through improved muscle health and physical activity. Moreover, the obtained results will provide a strong justification for rapid translation into clinical application.
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