Question: 

Critical illness myopathy (CIM) is a very common form of sepsis-related organ failure of skeletal muscle associated with prolonged weakness. Cellular studies suggest impaired Ca²⁺ homeostasis but no firm cellular mechanism has yet been established.

Methodology: 

Force/Ca²⁺ transients were recorded in skinned skeletal muscle fibres with a force transducer/confocal microscope upon SR Ca²⁺ release (caffeine or low Mg²⁺) under control conditions or after IL-1 incubation. SR leak was assessed in EGTA containing solutions and IL-1 action compared to tetracaine. IL-1-RyR1-interaction was assessed by co-IP and colocalization immunofluorescence microscopy. Membrane integrity after L-1-challenge in cultured fibres was monitored by propidium iodide.

Result: 

Consistently, caffeine-induced force/Ca²⁺ transients were larger after incubation with IL-1 compared to controls. However, low Mg²⁺-induced transients were merely blocked by IL-1. IL-1 reduced SR Ca²⁺ leak by ~20 %. The reduction of SR leak was via RyR1: the effect of 25 ng/l IL-1 was similar to ~100 mM tetracaine. Co-IP showed IL-1-RyR1 binding that was confirmed in single cell immuno-colocalization. Prolonged IL-1 challenge of intact single muscle cells in culture induced a compromised membrane integrity and intracellular accumulation of IL-1.

Conclusion: 

Our data show that IL-1 interacts with RyR1 in muscle and reduces SR Ca²⁺ leak. Although this should result in increased SR Ca²⁺ load for release, physiological Ca²⁺ release is impaired by IL-1's second action to stabilize the inhibitory Mg²⁺ binding site. Our study provides a novel and firm mechanism for muscle failure in septic patients that should inspire future clinical studies on drugs targeting IL-1.