EMD 57033 partially reverses ventilator-induced diaphragm muscle fibre calcium desensitisation
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In critically ill patients, ventilator-induced diaphragm muscle fibre dysfunction (VIDD) contributes to weaning problems, increasing hospitalisation time and related costs. VIDD pathophysiology remains partially unknown, especially the characterisation of the contractile dysfunction. In the present study, it was hypothesised that Ca2+ activation is affected during VIDD. Ca2+ sensitivity of contraction was therefore evaluated at the single skinned diaphragm muscle fibre level in piglets randomised into sham operation or 5-day mechanical ventilation. Ca2+ sensitivities of force and stiffness in fibres were significantly impaired in all mechanically ventilated piglets compared with sham-operated controls, suggesting a less efficient Ca2+ activation of cells, i.e. a lower relative number of strongly attached cross-bridges for each sub-maximal concentration of Ca2+. In an attempt to test whether this negative effect of VIDD is reversible, single muscle fibres were exposed to the EMD 57033 Ca2+ sensitiser. EMD 57033 (30 µM) improved the Ca2+ sensitivity of force and stiffness in fibres from animals that were mechanically ventilated for 5 days as well as in sham-operated piglets. Thus, EMD 57033 partly restored the Ca2+ activation of cells, reducing VIDD. This finding offers a strong basis for evaluating the effect of Ca2+ sensitisers on diaphragm function in vivo.
KeywordsMechanical ventilation Diaphragm muscle Porcine model Skinned fibre Ca2+ activation Ca2+ sensitizer
This study was supported by grants from the Swedish Institute and Association Française contre les Myopathies to J.O. and from the Swedish Research Council (08651), Association Française contre les Myopathies, Cancer Foundation and National Institutes of Health (AR045627, AR047318) to L.L. EMD 57033 was a gift from Dr. Norbert Beier from Merck KGaA, Darmstadt, Germany. We are grateful to Yvette Hedström and Ann-Marie Gustafsson for excellent technical assistance.
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