IL-1α Reversibly Inhibits Skeletal Muscle Ryanodine Receptor. A Novel Mechanism for Critical Illness Myopathy?

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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.

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