Secreted Frizzled-Related Protein 2 and Inflammation-Induced Skeletal Muscle Atrophy

• Published in: Critical care medicine Vol. 45; no. 2; p. e169
• Main Authors: Zhu, Xiaoxi, Kny, Melanie, Schmidt, Franziska, Hahn, Alexander, Wollersheim, Tobias, Kleber, Christian, Weber-Carstens, Steffen, Fielitz, Jens
• Format: Journal Article
• Language: English
• Published: United States 01.02.2017
• Subjects: Animals; Biopsy; Blotting, Western; Disease Models, Animal; Gene Expression Profiling; Humans; Inflammation - complications; Male; Membrane Proteins - adverse effects; Membrane Proteins - physiology; Mice; Mice, Inbred C57BL; Muscle Fibers, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscular Atrophy - chemically induced; Muscular Atrophy - etiology; Muscular Atrophy - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - physiology; Transforming Growth Factor beta1 - physiology
• ISSN: 1530-0293
• DOI: 10.1097/CCM.0000000000002056

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-β1 increases during inflammation and mediates muscle atrophy in vivo. We observed that the transforming growth factor-β1 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-β1-mediated effects and investigated the interrelationship between transforming growth factor-β1 and secreted frizzled-related protein 2 in inflammation-induced atrophy. Observational study and prospective animal trial. Two ICUs and research laboratory. 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. None. Gene set enrichment analysis uncovered transforming growth factor-β1 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-β1 through its cysteine-rich domain. Finally, secreted frizzled-related protein 2 prevented transforming growth factor-β1-induced atrophy in C2C12 myotubes. 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-β1-mediated atrophic effects in inflammation-induced atrophy.