title: IL-1α reversibly inhibits skeletal muscle ryanodine receptor. a novel mechanism for critical illness myopathy?
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 Ca(2+) fluorescence microscopy for force/Ca(2+) transients and Ca(2+) 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 Mg(2+) inhibition of Ca(2+) release. Low Mg(2+)-induced force and Ca(2+) transients were reversibly abolished by IL-1α. At normal Mg(2+), IL-1α reversibly increased caffeine-induced force and Ca(2+) transients. IL-1α reduced SR Ca(2+) leak via RyR1, as judged by (1) increased SR Ca(2+) retention, (2) increased IL-1α force transients being reproduced by 25 μM tetracaine, and (3) reduced Ca(2+) 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.
authors.affiliation: 1 Institute of Medical Biotechnology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Friedrich
authors.forename: Bing
authors.initials: B
authors.lastname: Yi
authors.forename: Joshua N
authors.initials: JN
authors.lastname: Edwards
authors.forename: Barbara
authors.initials: B
authors.lastname: Reischl
authors.forename: Anette
authors.initials: A
authors.lastname: Wirth-Hücking
authors.forename: Andreas
authors.initials: A
authors.lastname: Buttgereit
authors.forename: Roland
authors.initials: R
authors.lastname: Lang
authors.forename: Cornelia
authors.initials: C
authors.lastname: Weber
authors.forename: Fabian
authors.initials: F
authors.lastname: Polyak
authors.forename: Ilon
authors.initials: I
authors.lastname: Liu
authors.forename: Frederic
authors.initials: F
authors.lastname: von Wegner
authors.forename: Tanya R
authors.initials: TR
authors.lastname: Cully
authors.forename: Aven
authors.initials: A
authors.lastname: Lee
authors.forename: Patrick
authors.initials: P
authors.lastname: Most
authors.forename: Mirko
authors.initials: M
authors.lastname: Völkers
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D016638:Critical Illness; D007375:Interleukin-1 / Q000378:metabolism*; D008274:Magnesium / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D018908:Muscle Weakness / Q000378:metabolism; D009135:Muscular Diseases / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
chemical_list: D007375:Interleukin-1; D019837:Ryanodine Receptor Calcium Release Channel; D008274:Magnesium; D002118:Calcium