Critical illness myopathy serumfractions affect membrane excitability and intracellular calciumrelease in mammalian skeletal muscle

Abstract. The pathogenesis of myopathies occurring in critically illpatients (critical illnessmyopathy, CIM) is poorly understood. Both local andsystemic responses to sepsis and other severe insults to thebody are presumed to be involved but the precise mechanisms bywhich muscle function is impaired are far from clear. Toelucidate such mechanisms we investigated the effects of bloodserum fractions (5 kDa to 100 kDa molecular weight cut-off,MWCO) from patients with CIM and from control persons onmembrane and contractile functions in intact mammalian singleskeletal muscle fibres and chemically skinned fibre bundles. Inintact fibres, resting membrane potentials were less negativewhen exposed to CIM serum fractions compared with control serumfractions. Half-width and maximum rise time of action potentials(AP) were smaller in CIM serum low MWCO fractions vs. controlserum. Peak amplitudes of fast inward sodium currents(I_Na) were increased by low MWCO-CIMfractions compared with control sera fractions. Additionally,voltage dependent inactivation of I_Na wasshifted towards more positive potentials by high MWCO fractionsof CIM sera. In skinned fibres, pCa-force relations were similarin CIM and control serum fractions but peak force ofCa²⁺ induced force transients wasdecreased by low MWCO-CIM vs. control serum fractions. Ourresults (i) provide the first evidence that serum from CIMpatients affects membrane excitability and theexcitation-contraction coupling process at the level of thesarcoplasmic reticulum Ca²⁺ releaseof mammalian muscle fibres and (ii) also show that even controlserum fractions per se alter the response to importantphysiological membrane and contractility parameters comparedwith physiological saline.