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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-&bgr;1 increases during inflammation and mediates muscle atrophy in vivo. We observed that the transforming growth factor-&bgr;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-&bgr;1-mediated effects and investigated the interrelationship between transforming growth factor-&bgr;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-&bgr;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-&bgr;1 through its cysteine-rich domain. Finally, secreted frizzled-related protein 2 prevented transforming growth factor-&bgr;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-&bgr;1-mediated atrophic effects in inflammation-induced atrophy.