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


METHODS
Observational study and prospective animal trial.


METHODS
Two ICUs and research laboratory.


METHODS
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.


METHODS
None.


RESULTS
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.


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-β1-mediated atrophic effects in inflammation-induced atrophy.
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.
Xiaoxi
X
Zhu
Melanie
M
Kny
Franziska
F
Schmidt
Alexander
A
Hahn
Tobias
T
Wollersheim
Christian
C
Kleber
Steffen
S
Weber-Carstens
Jens
J
Fielitz
D000818:Animals; D001706:Biopsy; D015153:Blotting, Western; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000150:complications*; D008297:Male; D008565:Membrane Proteins / Q000009:adverse effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000187:drug effects; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009133:Muscular Atrophy / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D000094742:Secreted Frizzled-Related Proteins
D008565:Membrane Proteins; D053773:Transforming Growth Factor beta1; C109618:SFRP2 protein, human; D000094742:Secreted Frizzled-Related Proteins