Alterations in intracellular Ca2+-homeostasis of skeletal muscle fibers during sepsis*

Zink, Wolfgang; Kaess, Michael; Hofer, Stefan; Plachky, J.; Zausig, York; Sinner, Barbara; Weigand, Markus A.; Fink, Rainer H. A.; Graf, Bernhard M.

doi:10.1097/ccm.0b013e318170aa97

Cited by 31 publications

(38 citation statements)

References 37 publications

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“…However, myofibrillar protein loss always seems to affect actin and myosin likewise, at least in all studies investigating the time course of proteolysis up to ϳ20 h (200,290,291,776). It may be that a significant preferential myosin loss does not develop until longer times post-CLP, but this has not been experimentally proven although CLP in mice has been followed up until day seven, but not for protein contents in skeletal muscle (809). Thus this sepsis model has so far not qualified yet to reproduce all the pathological hallmarks seen in CIM, most importantly, preferential myosin loss, and is thus considered as sepsisinduced myopathy (SIM) under the ICUAW umbrella (FIG-URE 1B).…”

Section: E Rodent Sepsis Models (Clp and Lps Models)mentioning

confidence: 99%

“…However, in a steroid-denervation rat model of CIM, ORAI1 (Ca 2ϩ release-activated Ca 2ϩ channel protein 1) expression levels were found ϳ20% reduced compared with controls 7 days post-op (377). SR function in skeletal muscle still has only been initially studied in a CLP murine sepsis model by Zink et al (809). The authors compared "intracellular Ca 2ϩ regulation" in skinned EDL muscle fibers from CLP, sham-operated, and general-anaesthesiaonly mice 2-7 days post-procedure, recording caffeine-induced force transients.…”

Section: ؉ Transients In Critical Illnessmentioning

confidence: 99%

“…However, this approach is considered qualitative, at best, and has to be interpreted with caution. For example, their calculated Ca 2ϩ transient amplitudes in the general anesthesia group after 10 mM caffeine were close to 2 M and Ͻ1 M in the CLP group (809). However, direct Ca 2ϩ fluorescence recordings of Ca 2ϩ transients in rat EDL muscles using Magfura-2 already gave twitch peak Ca 2ϩ amplitudes of ϳ18 M (41).…”

Section: ؉ Transients In Critical Illnessmentioning

confidence: 99%

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

Friedrich

Reid

Berghe

et al. 2015

Physiological Reviews

300

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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Section: E Rodent Sepsis Models (Clp and Lps Models)mentioning

confidence: 99%

Section: ؉ Transients In Critical Illnessmentioning

confidence: 99%

Section: ؉ Transients In Critical Illnessmentioning

confidence: 99%

See 1 more Smart Citation

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

Friedrich

Reid

Berghe

et al. 2015

Physiological Reviews

300

329

View full text Add to dashboard Cite

show abstract

“…In skeletal muscle, the sarcoplasmic reticulum contributes to calcium homeostasis and is the organelle responsible in muscle for calcium binding and release. Sepsis has marked effects on calcium homeostasis, increasing intracellular calcium in limb skeletal muscle [86], reducing calcium binding in isolated sarcoplasmic reticular membrane [90], decreasing release of calcium from the sarcoplasmic reticulum and increasing the sensitivity of contractile proteins to calcium [91]. Several of these activities (e.g.…”

Section: Altered Function Of the Sarcoplasmic Reticulummentioning

confidence: 99%

Molecular mechanisms of intensive care unit-acquired weakness

Bloch¹,

Polkey²,

Griffiths³

et al. 2011

Eur Respir J

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Intensive care unit-acquired weakness (ICUAW) is an increasingly recognised and important clinical consequence of critical illness. It is associated with significant morbidity and mortality. The aetiology of this disease is not well understood. The purpose of this article is to review our understanding of the molecular pathogenesis of ICUAW in the context of current knowledge of clinical risk factors and aetiology.Key features of the disease are loss of muscle mass resulting from a shift in the dynamic balance of muscle protein synthesis and breakdown and a reduction in force-generating capacity. These alternations are secondary to neuropathy, disruption of the myofilament structure and function, a disrupted sarcoplasmic reticulum, electrical inexcitability and bioenergenetic failure.As knowledge and understanding of ICUAW grows, potential therapeutic targets will be identified, hopefully leading to multiple strategies for prevention and treatment of this important condition.

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“…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. During systemic inflammation, global and local cytokines are up-regulated (21).…”

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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Alterations in intracellular Ca2+-homeostasis of skeletal muscle fibers during sepsis*

Cited by 31 publications

References 37 publications

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

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

Molecular mechanisms of intensive care unit-acquired weakness

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

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