Increased muscle myofibrillar protein breakdown rates using 3-methylhistidine (tau-mHIS) stable isotopes in a Pseudomonas aeroginosa (PM) induced hyperdynamic sepsis pig model
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RationaleSepsis is characterized by severe muscle breakdown. Taumethylhistidine (mHIS) is generally considered a valuable marker of muscle myofibrillar protein breakdown. Quantitative measurement of the production of mHIS in urine is complicated due to factors like timing and correct sampling, meatfree diet requirement, and differences in mHIS metabolism between species. Therefore, we measured whole body mHis production (WbRa) using stable isotope technology during acute sepsis in the pig. We also examined organ mHis metabolism to establish the site of mHIS production.MethodIn 13 conscious postabsorptive pigs (25 kg) with intravenous PM induced hyperdynamic sepsis and 9 healthy controls, we measured mHISWbRa during a primed, constant and continuous infusion of L[tau2H3]mHIS stable isotope. Two hours before and between 14 and 18 hours during sepsis, we collected arterial plasma, and at 18 hours we obtained jejunum, jejunal mucosa scraping, ileum, liver, muscle and lung tissue. Enrichments of mHIS in plasma and intracellular pools were analyzed by LCMS/MS. WbRa was calculated with the tracer infusion rate and plasma mHIS steady state enrichment. Low mHIS enrichment in tissue in comparison to plasma enrichment defines a mHIS production site. Data are mean (SE) in nmol/kg bw/min; Fitting of plasma steady state enrichment curves, ANOVA and unpaired ttests were done by GraphPad Prism6.ResultsWe found increased WbRa values of mHIS 16 to 18h after sepsis induction in jejunal mucosa biopsies: 53.7(2.1) vs 37.2(1.9), p<0.0001. At t=18 h, we found low mHIS enrichments (25 (2.4)% of plasma enrichment, P<0.0001) only in muscle. Jejunum, jejunal mucosa scraping, ileum, liver, and lung tissue show higher enrichments than plasma (112(1.6)%, NS between tissues).ConclusionDuring acute severe sepsis in the pig, the increased whole body myofibrillar protein breakdown as measured in plasma during mHIS tracer infusion is fully related to muscle myofibrillar protein breakdown. We hypothesize that the use of mHIS stable isotope technology is a reliable tool to specifically measure changes in muscle myofibrillar protein breakdown in multiple species, including humans.Support or Funding InformationThis study was supported by NIH R01GM084447 and S10RR027047
