Secondary Logo

Institutional members access full text with Ovid®

Share this article on:

Temporally Distinct Regulation of Pathways Contributing to Cardiac Proteostasis During the Acute and Recovery Phases of Sepsis

Crowell, Kristen T.*; Moreno, Samantha§; Steiner, Jennifer L.; Coleman, Catherine S.; Soybel, David I.*,†,‡; Lang, Charles H.*,†

doi: 10.1097/SHK.0000000000001084
Basic Science Aspects
Editor's Choice

Background: Cardiac dysfunction is a common manifestation of sepsis and is associated with early increases in inflammation and decreases in myocardial protein synthesis. However, little is known regarding the molecular mechanisms regulating protein homeostasis during the recovery phase after the removal of the septic nidus. Therefore, the purpose of this study was to investigate diverse signal transduction pathways that regulate myocardial protein synthesis and degradation.

Methods: Adult male C57BL/6 mice were used to identify potential mechanisms mediating the acute (24 h) effect of cecal ligation and puncture as well as long-term changes that manifest during the chronic (10 days) recovery phase.

Results: Sepsis acutely decreased cardiac protein synthesis that was associated with reduced phosphorylation of S6K1/S6 but not 4E-BP1. Sepsis also decreased proteasome activity, although with no change in MuRF1 and atrogin-1 mRNA expression. Sepsis acutely increased apoptosis (increased caspase-3 and PARP cleavage), autophagosome formation (increased LC3B-II), and canonical inflammasome activity (increased NLRP3, TMS1, cleaved caspase-1). In contrast, during the recovery phase, independent of a difference in food consumption, global protein synthesis was increased, the early repression in proteasome activity was restored to basal levels, whereas stimulation of apoptosis, autophagosome formation, and the canonical inflammasome pathway had abated. However, during recovery there was a selective stimulation of the noncanonical inflammasome pathway as evidenced by activation of caspase-11 with cleavage of Gasdermin D.

Conclusions: These data demonstrate a temporally distinct homeostatic shift in the cardiac proteostatic response to acute infection and recovery.

*Department of Surgery, Penn State College of Medicine, Hershey, Pennsylvania

Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, Pennsylvania

Department of Nutritional Sciences, Penn State University, University Park, Pennsylvania

§Franklin and Marshal College, Lancaster, Pennsylvania

Address reprint requests to Charles H. Lang, PhD, Penn State College Medicine, Hershey, PA. E-mail: chl1@psu.edu

Received 13 October, 2017

Revised 2 November, 2017

Accepted 6 December, 2017

Authors’ contributions: All authors conceived and designed the study; collected, analyzed, and/or interpreted the data; and drafted and approved the final manuscript.

This work was supported by a grant from GM 38032 (CHL), as well as by postdoctoral fellowship awards F32 GM112401 (KTC), F32 AA023422 (JLS), and by an American Heart Association Summer Undergraduate Research Fellowship (14UFEL3900000) to Samantha Moreno.

The authors report no conflicts of interest.

© 2018 by the Shock Society