title: The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill.
abstract: Critical illness polyneuropathies (CIP) and myopathies (CIM) are common complications of critical illness. Several weakness syndromes are summarized under the term intensive care unit-acquired weakness (ICUAW). We propose a classification of different ICUAW forms (CIM, CIP, sepsis-induced, steroid-denervation myopathy) and pathophysiological mechanisms from clinical and animal model data. Triggers include sepsis, mechanical ventilation, muscle unloading, steroid treatment, or denervation. Some ICUAW forms require stringent diagnostic features; CIM is marked by membrane hypoexcitability, severe atrophy, preferential myosin loss, ultrastructural alterations, and inadequate autophagy activation while myopathies in pure sepsis do not reproduce marked myosin loss. Reduced membrane excitability results from depolarization and ion channel dysfunction. Mitochondrial dysfunction contributes to energy-dependent processes. Ubiquitin proteasome and calpain activation trigger muscle proteolysis and atrophy while protein synthesis is impaired. Myosin loss is more pronounced than actin loss in CIM. Protein quality control is altered by inadequate autophagy. Ca(2+) dysregulation is present through altered Ca(2+) homeostasis. We highlight clinical hallmarks, trigger factors, and potential mechanisms from human studies and animal models that allow separation of risk factors that may trigger distinct mechanisms contributing to weakness. During critical illness, altered inflammatory (cytokines) and metabolic pathways deteriorate muscle function. ICUAW prevention/treatment is limited, e.g., tight glycemic control, delaying nutrition, and early mobilization. Future challenges include identification of primary/secondary events during the time course of critical illness, the interplay between membrane excitability, bioenergetic failure and differential proteolysis, and finding new therapeutic targets by help of tailored animal models.
authors.affiliation: Institute of Medical Biotechnology, Department of Chemical and Biological Engineering, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany; College of Health and Human Performance, University of Florida, Gainesville, Florida; Clinical Department and Laboratory of Intensive Care Medicine, Division of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, Ohio; and Department of Physiology and Pharmacology, Department of Clinical Neuroscience, Clinical Neurophysiology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: O
authors.initials: O
authors.lastname: Friedrich
authors.affiliation: Institute of Medical Biotechnology, Department of Chemical and Biological Engineering, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany; College of Health and Human Performance, University of Florida, Gainesville, Florida; Clinical Department and Laboratory of Intensive Care Medicine, Division of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, Ohio; and Department of Physiology and Pharmacology, Department of Clinical Neuroscience, Clinical Neurophysiology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: M B
authors.initials: MB
authors.lastname: Reid
authors.affiliation: Institute of Medical Biotechnology, Department of Chemical and Biological Engineering, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany; College of Health and Human Performance, University of Florida, Gainesville, Florida; Clinical Department and Laboratory of Intensive Care Medicine, Division of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, Ohio; and Department of Physiology and Pharmacology, Department of Clinical Neuroscience, Clinical Neurophysiology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Van den Berghe
authors.affiliation: Institute of Medical Biotechnology, Department of Chemical and Biological Engineering, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany; College of Health and Human Performance, University of Florida, Gainesville, Florida; Clinical Department and Laboratory of Intensive Care Medicine, Division of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, Ohio; and Department of Physiology and Pharmacology, Department of Clinical Neuroscience, Clinical Neurophysiology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: I
authors.initials: I
authors.lastname: Vanhorebeek
authors.affiliation: Institute of Medical Biotechnology, Department of Chemical and Biological Engineering, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany; College of Health and Human Performance, University of Florida, Gainesville, Florida; Clinical Department and Laboratory of Intensive Care Medicine, Division of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, Ohio; and Department of Physiology and Pharmacology, Department of Clinical Neuroscience, Clinical Neurophysiology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Hermans
authors.affiliation: Institute of Medical Biotechnology, Department of Chemical and Biological Engineering, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany; College of Health and Human Performance, University of Florida, Gainesville, Florida; Clinical Department and Laboratory of Intensive Care Medicine, Division of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, Ohio; and Department of Physiology and Pharmacology, Department of Clinical Neuroscience, Clinical Neurophysiology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: M M
authors.initials: MM
authors.lastname: Rich
authors.affiliation: Institute of Medical Biotechnology, Department of Chemical and Biological Engineering, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany; College of Health and Human Performance, University of Florida, Gainesville, Florida; Clinical Department and Laboratory of Intensive Care Medicine, Division of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, Ohio; and Department of Physiology and Pharmacology, Department of Clinical Neuroscience, Clinical Neurophysiology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Larsson
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D016638:Critical Illness; D004195:Disease Models, Animal; D004734:Energy Metabolism; D056966:Excitation Contraction Coupling; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007362:Intensive Care Units; D007473:Ion Channels / Q000378:metabolism; D040542:Mechanotransduction, Cellular; D020409:Molecular Motor Proteins / Q000378:metabolism; D018908:Muscle Weakness / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy; D018482:Muscle, Skeletal / Q000294:innervation / Q000378:metabolism / Q000503:physiopathology*; D009135:Muscular Diseases / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy; D011115:Polyneuropathies / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy; D011237:Predictive Value of Tests; D012307:Risk Factors
chemical_list: D018836:Inflammation Mediators; D007473:Ion Channels; D020409:Molecular Motor Proteins