Upregulation of Heme Oxygenase-1 by Hemin Alleviates Sepsis-Induced Muscle Wasting in Mice.

Xiongwei Yu,Wenjun Han,Xiaoming Deng,Jinjun Bian,Changli Wang,Lulong Bo,Daming Sui

doi:10.1155/2018/8927104

Abstract

Hemin, an inducer of heme oxygenase-1 (HO-1), can enhance the activation of HO-1. HO-1 exhibits a variety of activities, such as anti-inflammatory, antioxidative, and antiapoptotic functions. The objective of this study was to investigate the effects of hemin on sepsis-induced skeletal muscle wasting and to explore the mechanisms by which hemin exerts its effects. Cecal ligation and perforation (CLP) was performed to create a sepsis mouse model. Mice were randomly divided into four groups: control, CLP, CLP plus group, and CLP-hemin-ZnPP (a HO-1 inhibitor). The weight of the solei from the mice was measured, and histopathology was examined. Cytokines were measured by enzyme-linked immunosorbent assay (ELISA). Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting were used to assess the expression levels of HO-1 and atrogin-1. Furthermore, we investigated the antioxidative effects of HO-1 by detecting malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity. CLP led to dramatic skeletal muscle weakness and atrophy, but pretreatment with hemin protected mice against CLP-mediated muscle atrophy. Hemin also induced high HO-1 expression, which resulted in suppressed proinflammatory cytokine and reactive oxygen species (ROS) production. The expression of MuRF1 and atrogin-1, two ubiquitin ligases of the ubiquitin-proteasome system- (UPS-) mediated proteolysis, was also inhibited by increased HO-1 levels. Hemin-mediated increases in HO-1 expression exert protective effects on sepsis-induced skeletal muscle atrophy at least partly by inhibiting the expression of proinflammatory cytokines, UPS-mediated proteolysis, and ROS activation. Therefore, hemin might be a new treatment target against sepsis-induced skeletal muscle atrophy.

Highlights

Sepsis is defined as a life-threatening organ dysfunction due to a dysregulated host response to infection [1]
There was no significant difference in the protein breakdown rates between the control and hemin groups, and the protein breakdown rates in the ZnPP group were similar to those in the Cecal ligation and perforation (CLP) group (Figure 1(c))
Because changes in proinflammatory cytokine levels play an important role in sepsis and may be involved in muscle atrophy, we examined the production of cytokines

Summary

Introduction

Sepsis is defined as a life-threatening organ dysfunction due to a dysregulated host response to infection [1]. A large number of critically ICU patients suffer from severe muscle wasting and impaired muscle function, which can delay respirator weaning and persist long after hospital discharge, reducing the patients’ quality of life [4, 5]. Protein degradation within muscle appears to rely on three pathways: ubiquitin-proteasome system- (UPS-) mediated proteolysis, autophagy, and calcium-dependent calpains [8]. MuRF1 and atrogin-1, are key positive regulators of UPS-mediated proteolysis and are upregulated in all rodent models of skeletal muscle atrophy [10,11,12]. These proteins have been widely used as markers of muscle wasting.

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