Mild Zinc Deficiency Augments Increased TNF‐α Expression But Not Decreased Muscle Protein Synthesis after Acute Sepsis

Abstract

Moderate Zinc (Zn) imbalances are common among the elderly and individuals with chronic inflammatory conditions such as obesity, diabetes and rheumatoid arthritis. Here we developed a mouse model to study the influence of such imbalance on innate immune and metabolic responses to polymicrobial sepsis. We hypothesize that pre‐existing, mild Zn deficiency amplifies the systemic inflammatory responses, thereby exacerbating the decrease in muscle protein synthesis observed in sepsis. In this study, adult male mice were fed a Zn adequate (ZA) or Zn deficient (ZD) diet (30 or 7 ppm Zn, respectively) over 4 weeks, and then were subjected to cecal ligation and puncture (CLP) and sacrificed 24 h later (n = 8‐11 mice/group). Acute mortality did not differ between either diet. Sepsis increased TNF‐α mRNA in muscle of ZA mice and further increased TNF‐α in ZD mice. The mRNA content of key Zn transporters ZnT2, Zip7 and Zip14 was increased in septic animals, although this increase did not differ with ZD. In both septic groups, the in vivo rate of skeletal muscle protein synthesis was similarly decreased as was the phosphorylation of 4E‐BP1, suggesting a down‐regulation of the mTOR pathway. The muscle‐specific E3 ubiquitin ligases atrogin‐1 and MuRF1 increased after sepsis, and ZD did not alter this increase. While mild Zn deficiency amplified the expression of some pro‐inflammatory cytokines, it did not further modulate protein synthesis, protein degradation, or the expression of Zn transporters in muscle during the acute phase of the septic response. Whether mild Zn deficiency negatively impacts convalescence during the recovery phase of sepsis remains to be assessed. (Supported by F32GM112401 and GM38032)