Secreted frizzled-related protein 2 and inflammation-induced skeletal muscle atrophy

Item Type:	Article
Title:	Secreted frizzled-related protein 2 and inflammation-induced skeletal muscle atrophy
Creators Name:	Zhu, X. and Kny, M. and Schmidt, F. and Hahn, A. and Wollersheim, T. and Kleber, C. and Weber-Carstens, S. and Fielitz, J.
Abstract:	OBJECTIVE: In sepsis, the disease course of critically ill patients is often complicated by muscle failure leading to ICU-acquired weakness. The myokine transforming growth factor-{beta}1 increases during inflammation and mediates muscle atrophy in vivo. We observed that the transforming growth factor-{beta}1 inhibitor, secreted frizzled-related protein 2, was down-regulated in skeletal muscle of ICU-acquired weakness patients. We hypothesized that secreted frizzled-related protein 2 reduction enhances transforming growth factor-{beta}1-mediated effects and investigated the interrelationship between transforming growth factor-{beta}1 and secreted frizzled-related protein 2 in inflammation-induced atrophy. DESIGN: Observational study and prospective animal trial. SETTING: Two ICUs and research laboratory. PATIENTS/SUBJECTS: Twenty-six critically ill patients with Sequential Organ Failure Assessment scores greater than or equal to 8 underwent a skeletal muscle biopsy from the vastus lateralis at median day 5 in ICU. Four patients undergoing elective orthopedic surgery served as controls. To search for signaling pathways enriched in muscle of ICU-acquired weakness patients, a gene set enrichment analysis of our recently published gene expression profiles was performed. Quantitative reverse transcriptase-polymerase chain reaction, Western blot, and immunohistochemistry were used to analyze secreted frizzled-related protein 2 expression and protein content. A mouse model of inflammation-induced skeletal muscle atrophy due to polymicrobial sepsis and cultured myocytes were used for mechanistic analyses. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Gene set enrichment analysis uncovered transforming growth factor-{beta}1 signaling activation in vastus lateralis from ICU-acquired weakness patients. Muscular secreted frizzled-related protein 2 expression was reduced after 5 days in ICU. Likewise, muscular secreted frizzled-related protein 2 expression was decreased early and continuously in mice with inflammation-induced atrophy. In muscle, secreted frizzled-related protein 2 was predominantly contained in fast twitch/type II myofibers. Secreted frizzled-related protein 2 physically interacted and colocalized with transforming growth factor-{beta}1 through its cysteine-rich domain. Finally, secreted frizzled-related protein 2 prevented transforming growth factor-{beta}1-induced atrophy in C2C12 myotubes. CONCLUSIONS: Muscular secreted frizzled-related protein 2 is down-regulated in ICU-acquired weakness patients and mice with inflammation-induced muscle atrophy. Decreased secreted frizzled-related protein 2 possibly establishes a positive feedback loop enhancing transforming growth factor-{beta}1-mediated atrophic effects in inflammation-induced atrophy.
Keywords:	Intensive Care Unit-Acquired Weakness, Secreted Frizzled-Related Protein 2, Sepsis, Skeletal Muscle Atrophy, Transforming Growth Factor-{beta}1, Animals, Inbred C57BL Mice, Mice
Source:	Critical Care Medicine
ISSN:	0090-3493
Publisher:	Lippincott Williams & Wilkins
Volume:	45
Number:	2
Page Range:	e169-e183
Date:	February 2017
Official Publication:	https://doi.org/10.1097/CCM.0000000000002056
PubMed:	View item in PubMed

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