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Dysregulation of sodium channel gating in critical illness myopathy

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Abstract

Critical illness myopathy (CIM) is the most common caused of acquired weakness in critically ill patients. While atrophy of muscle fibers causes weakness, the primary cause of acute weakness is loss of muscle excitability. Studies in an animal model of CIM suggest that both depolarization of the resting potential and a hyperpolarized shift in the voltage dependence of sodium channel gating combine to cause inexcitability. In active adult skeletal muscle the only sodium channel isoform expressed is Nav1.4. In the animal model of CIM the Nav1.5 sodium channel isoform is upregulated, but the majority of sodium current is still carried by Nav1.4 sodium channels. Experiments using toxins to selectively bock the Nav1.4 isoform demonstrated that the cause of the hyperpolarized shift in sodium channel inactivation is a hyperpolarized shift in inactivation of the Nav1.4 isoform. These data suggest that CIM represents a new type of ion channel disease in which altered gating of sodium channels is due to improper regulation of the channels rather than mutation of channels or changes in isoform expression. The hypothesis that dysregulation of sodium channel gating underlies inexcitability of skeletal muscle in CIM raises the possibility that there maybe dysregulation of sodium channel gating in other tissues in critically ill patients. We propose that there is a syndrome of reduced electrical excitability in critically ill patients that affects skeletal muscle, peripheral nerve, the heart and central nervous system. This syndrome manifests as CIM, critical illness polyneuropathy, reduced cardiac contractility and septic encephalopathy.

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Acknowledgements

This work was supported by National Institutes of Health grant NS040826 (M. M. Rich).

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Authors and Affiliations

  1. Department of Neurology, University of Michigan Health Systems, Ann Arbor, MI, 48109, USA

    James W. Teener

  2. Neuroscience, Cell Biology and Physiology (NCBP), Wright State University, 014 M and M, Dayton, OH, 45435, USA

    Mark M. Rich

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  1. James W. Teener
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  2. Mark M. Rich
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Correspondence to Mark M. Rich.

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Teener, J.W., Rich, M.M. Dysregulation of sodium channel gating in critical illness myopathy. J Muscle Res Cell Motil 27, 291–296 (2006). https://doi.org/10.1007/s10974-006-9074-5

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  • DOI: https://doi.org/10.1007/s10974-006-9074-5

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