Impact of post-synaptic block of neuromuscular transmission, muscle unloading and mechanical ventilation on skeletal muscle protein and mRNA expression

Norman, Holly S.; Nordquist, Jenny; Andersson, P.; Ansved, Tor; Tang, Xiao; Dworkin, Barry R.; Larsson, Lars

doi:10.1007/s00424-006-0110-5

Cited by 43 publications

(66 citation statements)

References 56 publications

(59 reference statements)

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“…The results from this study and a previous study focusing on myofibrillar protein and mRNA expression (32) have documented the usefulness of this model for future and more detailed studies of muscle wasting in ICU patients. The model enables time-resolved studies, as well as studies regarding mechanical ventilation, neuromuscular blockade, muscle unloading, and corticosteroid treatment separately and in different combinations.…”

Section: Experimental Set-upsupporting

confidence: 57%

“…We observed a general downregulation of all these transcripts, except for myosin-binding protein H, indicating that the muscle wasting in the ICU is associated with a decreased protein synthesis (32). In addition to the lowered levels of TRα1, which has a role in myosin isoform switching (above), we have also identified NFATc1 as a potential mediator of the reduced transcription.…”

Section: Pathways In Protein Synthesismentioning

confidence: 62%

“…BLASTsearches revealed no cross-reactivity toward any other DNA sequences in rat. RNA purification, cDNA synthesis, and PCR (run on an MyiQ™ instrument; BioRad, Hercules, CA, USA) were performed as described previously (32). Threshold cycle (C T ) data obtained from running real-time RT-PCR was related to a standard curve to obtain the starting quantity (SQ) of the template cDNA, and the values were normalized against 18S rRNA (32).…”

Section: Real-time Rt-pcrmentioning

confidence: 99%

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Transcription Factors in Muscle Atrophy Caused by Blocked Neuromuscular Transmission and Muscle Unloading In Rats

Nordquist

Höglund

Norman

et al. 2007

Mol Med

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The muscle wasting associated with long-term intensive care unit (ICU) treatment has a negative effect on muscle function resulting in prolonged periods of rehabilitation and a decreased quality of life. To identify mechanisms behind this form of muscle wasting, we have used a rat model designed to mimic the conditions in an ICU. Rats were pharmacologically paralyzed with a postsynaptic blocker of neuromuscular transmission, and mechanically ventilated for one to two weeks, thereby unloading the limb muscles. Transcription factors were analyzed for cellular localization and nuclear concentration in the fast-twitch muscle extensor digitorum longus (EDL) and in the slow-twitch soleus. Significant muscle wasting and upregulation of mRNA for the ubiquitin ligases MAFbx and MuRF1 followed the treatment. The IκB family-member Bcl-3 displayed a concomitant decrease in concentration, suggesting altered κB controlled gene expression, although NFκB p65 was not significantly affected. The nuclear levels of the glucocorticoid receptor (GR) and the thyroid receptor α1 (TRα1) were altered and also suggested as potential mediators of the MAFbx-and MuRF1-induction in the absence of induced Foxo1. We believe that this model, and the strategy of quantifying nuclear proteins, will provide a valuable tool for further, more detailed, analyses of the muscle wasting occurring in patients kept on a mechanical ventilator. variations in the response. For example, cachexia associated with disease states such as cancer and sepsis involves an increase in inflammatory cytokine production, which activates transcription factors that are, at least partly, distinct from those activated by disuse (12). How, and if, these differences affect the net result of the atrophic process is still unclear.Muscle wasting and impaired muscle function impose a risk to critically ill ICU patients during treatment. Specifically, neuromuscular abnormalities have been reported as the dominant cause for the reduced quality of life in critically ill ICU survivors, and are remaining even up to two years after hospital discharge (13,14). Therefore, our research is focused on the molecular events mediating the muscle atrophy in ICU patients, because successful treatment of this side effect would be highly beneficial for the survival, recovery, and quality of life in these patients. To address this issue, we have used an experimental rat model mimicking the conditions for many ICU patients, such as mechanical ventilation for long durations (weeks), postsynaptic block of neuromuscular transmission to facilitate ventilation, and unloading of muscles. In this study, the levels of a number of transcription factors in nuclear extracts from muscle tissue, and their spatial organization in the muscle fiber, have been investigated. The transcription factors we selected for investigation had been implicated in the expression of MAFbx and MuRF1 or as downstream effectors of signal transduction pathways previously linked to muscle atrophy or in the regulation of differentiation an...

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Section: Experimental Set-upsupporting

confidence: 57%

Section: Pathways In Protein Synthesismentioning

confidence: 62%

Section: Real-time Rt-pcrmentioning

confidence: 99%

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Transcription Factors in Muscle Atrophy Caused by Blocked Neuromuscular Transmission and Muscle Unloading In Rats

Nordquist

Höglund

Norman

et al. 2007

Mol Med

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“…Although the exact underlying mechanisms for the diaphragm weakness are not known, these findings may point towards an altered quality of acto-myosin interactions in the affected diaphragm where also the loading pattern would be changed during ICU management (133,511,517,518). Interestingly, in intercostal muscles, there is a similar decline in myosin-to-actin ratio as in the limb muscle (512). Thus it may be speculated that the passive loading of the diaphragm by the mechanical ventilator (72 times/min in the rat model) had an impact on transcriptional regulation of myofibrillar protein synthesis but not on the activation of protein degradation pathways.…”

Section: Rodent Icu Modelmentioning

confidence: 98%

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

Friedrich

Reid

Berghe

et al. 2015

Physiological Reviews

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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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“…A central issue is whether denervation of muscle mimics the effects of unloading muscle caused by neuromuscular blocking agents in patients. A recent study compared muscle treated with denervation alone to muscle treated with the combination of neuromuscular blockade and corticosteroids and found differences (42). We have previously found that the addition of corticosteroids to denervation has profound effects on muscle (47,48), which suggests the differences were likely due to treatment with corticosteroids rather than difference between denervation and neuromuscular block.…”

mentioning

confidence: 92%

Upregulation of the Ca_V1.1-ryanodine receptor complex in a rat model of critical illness myopathy

Kraner

Wang

Novak

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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The processes that trigger severe muscle atrophy and loss of myosin in critical illness myopathy (CIM) are poorly understood. It has been reported that muscle disuse alters Ca2+ handling by the sarcoplasmic reticulum. Since inactivity is an important contributor to CIM, this finding raises the possibility that elevated levels of the proteins involved in Ca2+ handling might contribute to development of CIM. CIM was induced in 3- to 5-mo-old rats by sciatic nerve lesion and infusion of dexamethasone for 1 wk. Western blot analysis revealed increased levels of ryanodine receptor (RYR) isoforms-1 and -2 as well as the dihydropyridine receptor/voltage-gated calcium channel type 1.1 (DHPR/CaV 1.1). Immunostaining revealed a subset of fibers with elevation of RYR1 and CaV 1.1 that had severe atrophy and disorganization of sarcomeres. These findings suggest increased Ca2+ release from the sarcoplasmic reticulum may be an important contributor to development of CIM. To assess the endogenous functional effects of increased intracellular Ca2+ in CIM, proteolysis of α-fodrin, a well-known target substrate of Ca2+-activated proteases, was measured and found to be 50% greater in CIM. There was also selective degradation of myosin heavy chain relative to actin in CIM muscle. Taken together, our findings suggest that increased Ca2+ release from the sarcoplasmic reticulum may contribute to pathology in CIM.

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Impact of post-synaptic block of neuromuscular transmission, muscle unloading and mechanical ventilation on skeletal muscle protein and mRNA expression

Cited by 43 publications

References 56 publications

Transcription Factors in Muscle Atrophy Caused by Blocked Neuromuscular Transmission and Muscle Unloading In Rats

Transcription Factors in Muscle Atrophy Caused by Blocked Neuromuscular Transmission and Muscle Unloading In Rats

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

Upregulation of the Ca_V1.1-ryanodine receptor complex in a rat model of critical illness myopathy

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Impact of post-synaptic block of neuromuscular transmission, muscle unloading and mechanical ventilation on skeletal muscle protein and mRNA expression

Cited by 43 publications

References 56 publications

Transcription Factors in Muscle Atrophy Caused by Blocked Neuromuscular Transmission and Muscle Unloading In Rats

Transcription Factors in Muscle Atrophy Caused by Blocked Neuromuscular Transmission and Muscle Unloading In Rats

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

Upregulation of the CaV1.1-ryanodine receptor complex in a rat model of critical illness myopathy

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Product

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Upregulation of the Ca_V1.1-ryanodine receptor complex in a rat model of critical illness myopathy