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Enhanced muscle shortening and impaired Ca2+ channel function in an acute septic myopathy model

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Abstract

Myopathies in critically ill patients are increasingly documented. Various animal models of chronic sepsis have been employed to investigate reduced membrane excitability or altered isometric contractility of skeletal muscle. In contrast, immediate changes occurring during acute sepsis are significantly under-characterised; L-type Ca2+ channel function or isotonic shortening are examples. We recorded slowly activating L-type Ca2+ currents (I Ca) in voltage-clamped single intact mouse skeletal muscle fibres and tested the effects of acute challenge with serum fractions from critical illness myopathy patients (CIM). Using a high-speed camera system, we simultaneously recorded unloaded fibre shortening during isotonic contractions with unprecedented temporal resolution (~1,600 frames/s). Time courses of fibre lengths and shortening velocity were determined from automated imaging algorithms. CIM fractions acutely induced depression of I Ca amplitudes with no shifts in I Ca–V-relations. Voltage-dependent inactivation was unaltered and I Ca activation and inactivation kinetics were prolonged compared to controls. Unexpectedly, maximum unloaded speed of shortening was slightly faster following CIM serum applications, suggesting a direct action of CIM serum on weak-binding-state cross-bridges. Our results are compatible with a model where CIM serum might acutely reduce a fraction of functional L-type Ca2+ channels and could account for reduced SR Ca2+ release and force production in CIM patients. Acute increase in isotonic shortening velocity might be an early diagnostic feature suitable for testing in clinical studies. The acute challenge model is also robust against atrophy or fibre type changes that ordinarily would have to be considered in chronic sepsis models.

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Abbreviations

CIM:

Critical illness myopathy

CS:

Control sera

I Ca :

L-type Ca2+ current

DHPR:

Dihydropyridine receptor

MWCO:

Molecular weight cut-off

RyR:

Ryanodine receptor

SR:

Sarcoplasmic reticulum

τdec I Ca :

Inactivation time constant

TTP I Ca :

Time-to-peak

v u :

Unloaded shortening speed

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Acknowledgments

This study was supported by a Faculty Grant from the Medical Faculty of the Ruprecht-Karls-University (F.203694) and through an Australian Research Council International Fellowship (ARCIF) awarded to one of the authors (OF).

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Authors and Affiliations

  1. Medical Biophysics, Department of Systems Physiology, Institute of Physiology and Pathophysiology, University of Heidelberg, INF 326, 69120, Heidelberg, Germany

    Oliver Friedrich & Frederic von Wegner

  2. School of Biomedical Sciences, University of Queensland, Brisbane, QLD, 4072, Australia

    Oliver Friedrich

  3. Department of Neurology, University of Heidelberg, INF 400, Heidelberg, Germany

    Ernst Hund

  4. Brain Imaging Centre, Johann Wolfgang Goethe University, Schleusenweg 2-16, 60528, Frankfurt am Main, Germany

    Frederic von Wegner

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  1. Oliver Friedrich
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Correspondence to Oliver Friedrich.

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Friedrich, O., Hund, E. & von Wegner, F. Enhanced muscle shortening and impaired Ca2+ channel function in an acute septic myopathy model. J Neurol 257, 546–555 (2010). https://doi.org/10.1007/s00415-009-5362-5

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  • DOI: https://doi.org/10.1007/s00415-009-5362-5

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