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Principal Investigator: Nicolaas E Deutz
Organization: TEXAS A&M UNIVERSITY
Fiscal Year: 2024
Award: $457,498
Funding agency: National Institute of General Medical Sciences
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.
Terms: <(TNF)-α><3-hydroxy-3-methylbutyric acid><3-hydroxyisovaleric acid><APF-1><ATP-Dependent Proteolysis Factor 1><Abnormal Assessment of Metabolism><Acceleration><Acute><Amino Acids><Animal Model><Animal Models and Related Studies><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Attenuated><Autophagocytosis><B-Cell Differentiation Factor Gene><B-Cell Stimulatory Factor 2 Gene><BSF-2 Gene><BSF2 Gene><Behavior><Beta-2 Gene Interferon><Biopsy><Blood Plasma><Body Tissues><CSIF><CSIF-10><Cachectin><Catabolism><Catheterization><Clinical><Complication><Critical Illness><Critically Ill><Cytokine Synthesis Inhibitory Factor><Death Rate><Development><Dietary Intervention><Disease><Disorder><Double-Blind Method><Double-Blind Study><Double-Blinded><Double-Masked Method><Double-Masked Study><Dysfunction><Essential Amino Acids><Evaluation><Family suidae><Fatigue><Formulation><Foundations><Functional disorder><Glutathione><Goals><HMB-d6><HMG-20><HSF Gene><Health><Hepatocyte Stimulatory Factor Gene><High Mobility Protein 20><Hour><Human><Human Characteristics><Human Nature><Hybridoma Growth Factor Gene><IFNB2 Gene><IL-10><IL-6 Gene><IL10><IL10A><IL6><IL6 gene><Impairment><Infection><Interleukin 10 Precursor><Interleukin 6 (Interferon, Beta 2) Gene><Interleukin-10><Interleukin-6 Gene><Kinetics><Knowledge><Lack of Energy><Life><Liver><Macrophage-Derived TNF><Medical Rehabilitation><Membrane Transport><Metabolic><Metabolic Pathway><Metabolic Studies><Metabolism Studies><Methodology><Miscellaneous Antibiotic><Modeling><Modern Man><Molecular><Monitor><Monocyte-Derived TNF><Morbidity><Morbidity - disease rate><Muscle><Muscle Atrophy><Muscle Fatigue><Muscle Proteins><Muscle Tissue><Muscle Weakness><Muscle function><Muscle rehabilitation><Muscular Atrophy><Muscular Fatigue><Muscular Weakness><Nature><Nutrient><Nutrition Interventions><Nutritional><Nutritional Interventions><Nutritional Support><Organ><Outcome><P aeruginosa><P. aeruginosa><Patients><Physical activity><Physiopathology><Pigs><Placebos><Plasma><Plasma Serum><Production><Protein Biosynthesis><Proteins><Pseudomonas aeruginosa><Pseudomonas pyocyanea><Public Health><Randomized><Recovery><Rehabilitation><Rehabilitation therapy><Research><Reticuloendothelial System, Serum, Plasma><Ribosomal Peptide Biosynthesis><Ribosomal Protein Biosynthesis><Ribosomal Protein Synthesis><Sampling><Sepsis><Sham Treatment><Signal Pathway><Skeletal Muscle><Suidae><Supplementation><Swine><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Technology><Testing><Therapeutic><Tissues><Tracer><Translations><Transmembrane Transport><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Ubiquitin><Voluntary Muscle><aminoacid><arm><assess effectiveness><attenuate><attenuates><autophagy><beta-hydroxy-beta-methylbutyrate><beta-hydroxyisovaleric acid><beta-hydroxymethylbutyrate><blood infection><bloodstream infection><clinical applicability><clinical application><clinical relevance><clinically relevant><cognitive rehab><cognitive rehabilitation><combat><cost effective><design><designing><determine effectiveness><developmental><diet intervention><effectiveness assessment><effectiveness evaluation><evaluate effectiveness><examine effectiveness><functional outcomes><gamma-L-Glu-L-Cys-Gly><gamma-L-Glutamyl-L-Cysteinylglycine><hepatic body system><hepatic organ system><improved><innovate><innovation><innovative><insight><loss of function><metabolic abnormality assessment><model of animal><mortality rate><mortality ratio><muscle breakdown><muscle bulk><muscle degradation><muscle deterioration><muscle form><muscle loss><muscle mass><muscle strength><muscle wasting><muscular><new approaches><novel><novel approaches><novel strategies><novel strategy><nutrition><nutritional approach><nutritional care><nutritional supplementation><nutritional therapy><nutritious><pathophysiology><pig model><piglet model><porcine><porcine model><primary end point><primary endpoint><protein homeostasis><protein metabolism><protein synthesis><proteostasis><randomisation><randomization><randomly assigned><rehab therapy><rehabilitative><rehabilitative therapy><response><sensor><sham therapy><suid><swine model><translation><translation to humans><translational model><wasting><β-hydroxy β-methylbutyric acid><β-hydroxy-β-methylbutyrate><β-hydroxyisovaleric acid><β-hydroxymethylbutyrate>