• Xiaoxi Zhu, Melanie Kny, Franziska Schmidt, Alexander Hahn, Tobias Wollersheim, Christian Kleber, Steffen Weber-Carstens, and Jens Fielitz.
• 1Department of Molecular Cardiology, Experimental and Clinical Research Center (ECRC), Charité-Universitätsmedizin Berlin, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany. 2Department of Anesthesiology and Operative Intensive Care Medicine, Campus Virchow and Campus Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany. 3Berlin Institute of Health (BIH), Kapelle-Ufer 2, Berlin, Germany. 4Center for Musculoskeletal Surgery, Campus Virchow, Charité-Universitätsmedizin Berlin, Berlin, Germany. 5Department of Cardiology, Heart Center Brandenburg and Medical University Brandenburg (MHB), Bernau, Germany.
• Crit. Care Med. 2017 Feb 1; 45 (2): e169-e183.

ObjectiveIn 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.DesignObservational study and prospective animal trial.SettingTwo ICUs and research laboratory.Patients/SubjectsTwenty-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.InterventionsNone.Measurements And Main ResultsGene 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.ConclusionsMuscular 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.

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