Effects of chronic sepsis on contractile properties of fast twitch muscle in an experimental model of critical illness neuromyopathy in the rat

Rossignol, Benoît; Guéret, Gildas; Pennec, Jean-Pierre; Morel, Julie; Rannou, Fabrice; Giroux-Metgès, Marie-Agnès; Talarmin, Hélène; Gioux, M.; Arvieux, C. C.

doi:10.1097/ccm.0b013e318176106b

Cited by 52 publications

(58 citation statements)

References 38 publications

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“…Following cecal ligation and puncture, reduced contractile force and increased fatigue were shown in rat soleus at 7 days (7), and extensor digitorum longus at 10 days (8). In both these studies, the distal tendon was attached to a force transducer with complete denervation of the surrounding musculature.…”

Section: Discussionmentioning

confidence: 99%

“…Models examining the prolonged recovery phase of critical illness are rare, despite inadequate recovery being increasingly recognized as having a major negative impact upon long-term quality of life (2,5). Muscle biopsies from affected patients confirm significant atrophy and wasting (6)(7)(8)(9)(10), though direct inferences from single fiber level pathology to functional tests of muscle strength and fatigue are limited.…”

Section: Introductionmentioning

confidence: 99%

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Detailed Characterization of a Long-Term Rodent Model of Critical Illness and Recovery

Hill

Saeed

Phadke

et al. 2015

Critical Care Medicine

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Objective: To characterize a long-term model of recovery from critical illness, with particular emphasis on cardiorespiratory, metabolic and muscle function Design: Randomized controlled animal study Setting: University research laboratory Subjects: Male Wistar ratsInterventions: Intraperitoneal injection of the fungal cell wall constituent, zymosan or n-saline. Measurements and Main Results:Following intervention, rats were followed for up to two weeks.Animals with zymosan peritonitis reached a clinical and biochemical nadir on day 2. Initial reductions were seen in body weight, total body protein and fat, and muscle mass. Leg muscle fiber diameter remained subnormal at 14 days with evidence of persisting myonecrosis, even though gene expression of regulators of muscle mass (e.g. MAFbx, MURF1, myostatin) had peaked on days 2-4 but had normalized by Day 7. Treadmill exercise capacity, forelimb grip strength and in vivo maximum tetanic force were also reduced. Food intake was minimal until Day 4 but increased thereafter. This did not relate to appetite hormone levels with early (6h) rises in plasma insulin and leptin followed by persisting subnormal levels; ghrelin levels did not change. Serum IL-6 level peaked at 6h but had normalized by Day 2 whereas IL-10 remained persistently elevated and HDL cholesterol persistently depressed. There was an early myocardial depression and rise in core temperature, yet reduced oxygen consumption and respiratory exchange ratio with a loss of diurnal rhythmicity that showed a gradual but incomplete recovery by Day 7.Conclusions: This detailed physiological, metabolic, hormonal, functional and histological muscle characterization of a model of critical illness and recovery reproduces many of the findings reported in human critical illness. It can be used to assess putative therapies that may attenuate loss, or enhance recovery, of muscle mass and function.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Detailed Characterization of a Long-Term Rodent Model of Critical Illness and Recovery

Hill

Saeed

Phadke

et al. 2015

Critical Care Medicine

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“…In a follow-up study, Niiya et al (508) focused on elucidating the exact mechanisms underlying changes in neuromuscular transmission during "acute late" sepsis (ϳ18 h post CLP). This was because results from chronic sepsis either in nonlethal panperitonitis CLP models or intraperitoneal endotoxininduced sepsis in animals were inconclusive, showing either hyper-or hyposensitivity to d-tubocurarine, or a decrease or no change at all in AChR number (313,595,720). Acute late sepsis (ϳ18 h post CLP) induced a significant increase in endplate potential (EPP; postjunctional potential induced by quantal release of acetylcholine from the motor nerve bouton in response to electric stimulation) amplitudes and EPP quantal content, indicating a facilitation of EPPs and excitability of muscle (508).…”

Section: B Neuromuscular Transmission In Sepsis and Systemic Inflammmentioning

confidence: 99%

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

Friedrich

Reid

Berghe

et al. 2015

Physiological Reviews

291

329

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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 2ϩ dysregulation is present through altered Ca 2ϩ 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.

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“…Skeletal muscles mostly affected are limb muscles and the diaphragm, which translates to the symptoms seen in affected patients (i.e., acute quadriplegia or weaning failure [14]). Experimental approaches that cover the sepsis aspect of CIM range from LPS- (15) to cecal-ligation and puncture-induced sepsis (16), as well as acute septic serum challenge in vitro models (17), whereas other trigger factors apart from inflammation have been employed using steroid-denervation animal models (18). Although decreased membrane excitability (15,18), decreased contractility and increased fatigability (16), or metabolic failure (19) have been noted across all different conditioning models, findings for altered Ca 21 homeostasis (20) have been only descriptive, and events that coin the mechanism of CIM have not been unraveled.…”

mentioning

confidence: 99%

IL-1α Reversibly Inhibits Skeletal Muscle Ryanodine Receptor. A Novel Mechanism for Critical Illness Myopathy?

Friedrich

Edwards

et al. 2014

Am J Respir Cell Mol Biol

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Critical illness myopathies in patients with sepsis or sustained mechanical ventilation prolong intensive care treatment and threaten both patients and health budgets; no specific therapy is available. Underlying pathophysiological mechanisms are still patchy. We characterized IL-1a action on muscle performance in "skinned" muscle fibers using force transducers and confocal Ca (1) increased SR Ca 21 retention, (2) increased IL-1a force transients being reproduced by 25 mM tetracaine, and (3) reduced Ca 21 spark frequencies by IL-1a or tetracaine. Coimmunoprecipitation confirmed RyR1/IL-1 association. RyR1/IL-1 immunofluorescence patterns perfectly colocalized. Long-term, 8-hour IL-1a challenge of intact muscle fibers compromised membrane integrity in approximately 50% of fibers, and confirmed intracellular IL-1a deposition. IL-1a exerts a novel, specific, and reversible interaction mechanism with the skeletal muscle RyR1 macromolecular release complex without the need to act via its membrane IL-1 receptor, as IL-1R membrane expression levels were not detectable in Western blots or immunostaining of single fibers. We present a potential explanation of how the inflammatory mediator, IL-1a, may contribute to muscle weakness in critical illness.

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Effects of chronic sepsis on contractile properties of fast twitch muscle in an experimental model of critical illness neuromyopathy in the rat

Abstract: Chronic inflammation and sepsis induced a decrease in contractile performances of extensor digitorum longus along with accelerated kinetics of atracurium possibly induced by modified expression of RyR1 receptors and not acetylcholine-receptors.

Cited by 52 publications

References 38 publications

Detailed Characterization of a Long-Term Rodent Model of Critical Illness and Recovery

Detailed Characterization of a Long-Term Rodent Model of Critical Illness and Recovery

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

IL-1α Reversibly Inhibits Skeletal Muscle Ryanodine Receptor. A Novel Mechanism for Critical Illness Myopathy?

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