IL-1α reversibly inhibits skeletal muscle ryanodine receptor. A novel mechanism for critical illness myopathy?

Friedrich, Oliver, Yi, Bing, Edwards, Joshua N., Reischl, Barbara, Wirth-Hucking, Anette, Buttgereit, Andreas, Lang, Roland, Weber, Cornelia, Polyak, Fabian, Liu, Ilon, von Wegner, Frederic, Cully, Tanya R., Lee, Aven, Most, Patrick and Volkers, Mirko (2014) IL-1α reversibly inhibits skeletal muscle ryanodine receptor. A novel mechanism for critical illness myopathy?. American Journal of Respiratory Cell and Molecular Biology, 50 6: 1096-1106. doi:10.1165/rcmb.2013-0059OC

Author Friedrich, Oliver
Yi, Bing
Edwards, Joshua N.
Reischl, Barbara
Wirth-Hucking, Anette
Buttgereit, Andreas
Lang, Roland
Weber, Cornelia
Polyak, Fabian
Liu, Ilon
von Wegner, Frederic
Cully, Tanya R.
Lee, Aven
Most, Patrick
Volkers, Mirko
Title IL-1α reversibly inhibits skeletal muscle ryanodine receptor. A novel mechanism for critical illness myopathy?
Journal name American Journal of Respiratory Cell and Molecular Biology   Check publisher's open access policy
ISSN 1535-4989
Publication date 2014-06
Year available 2014
Sub-type Article (original research)
DOI 10.1165/rcmb.2013-0059OC
Open Access Status
Volume 50
Issue 6
Start page 1096
End page 1106
Total pages 11
Place of publication New York, NY, United States
Publisher American Thoracic Society
Collection year 2015
Language eng
Formatted abstract
Critical illness myopathies in patients with sepsis or sustained mechanical ventilation prolong intensive care treatment and threaten both patients and health budgets; no specific therapy is available. Underlying pathophysiological mechanisms are still patchy. We characterized IL-1α action on muscle performance in “skinned” muscle fibers using force transducers and confocal Ca2+ fluorescence microscopy for force/Ca2+ transients and Ca2+ sparks. Association of IL-1α with sarcoplasmic reticulum (SR) release channel, ryanodine receptor (RyR) 1, was investigated with coimmunoprecipitation and confocal immunofluorescence colocalization. Membrane integrity was studied in single, intact fibers challenged with IL-1α. IL-1α reversibly stabilized Mg2+ inhibition of Ca2+ release. Low Mg2+–induced force and Ca2+ transients were reversibly abolished by IL-1α. At normal Mg2+, IL-1α reversibly increased caffeine-induced force and Ca2+ transients. IL-1α reduced SR Ca2+ leak via RyR1, as judged by (1) increased SR Ca2+ retention, (2) increased IL-1α force transients being reproduced by 25 μM tetracaine, and (3) reduced Ca2+ spark frequencies by IL-1α or tetracaine. Coimmunoprecipitation confirmed RyR1/IL-1 association. RyR1/IL-1 immunofluorescence patterns perfectly colocalized. Long-term, 8-hour IL-1α challenge of intact muscle fibers compromised membrane integrity in approximately 50% of fibers, and confirmed intracellular IL-1α deposition. IL-1α exerts a novel, specific, and reversible interaction mechanism with the skeletal muscle RyR1 macromolecular release complex without the need to act via its membrane IL-1 receptor, as IL-1R membrane expression levels were not detectable in Western blots or immunostaining of single fibers. We present a potential explanation of how the inflammatory mediator, IL-1α, may contribute to muscle weakness in critical illness.
Keyword Cytokines
Ryanodine receptor 1
Critical illness myopathy
Ca2+ regulation
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Biomedical Sciences Publications
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