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Intensive Care Unit Muscle Wasting: Skeletal Muscle Phenotype and Underlying Molecular Mechanisms
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
2012 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Acute quadriplegic myopathy (AQM), or critical illness myopathy, is a common debilitating acquired disorder in critically ill intensive care unit (ICU) patients characterized by generalized muscle wasting and weakness of limb and trunk muscles. A preferential loss of the thick filament protein myosin is considered pathognomonic of this disorder, but the myosin loss is observed relatively late during the disease progression. In attempt to explore the potential role of factors considered triggering AQM in sedated mechanically ventilated (MV) ICU patients, we have studied the early effects, prior to the myosin loss, of neuromuscular blockade (NMB), corticosteroids (CS) and sepsis separate or in combination in a porcine experimental ICU model. Specific interest has been focused on skeletal muscle gene/protein expression and regulation of muscle contraction at the muscle fiber level. This project aims at improving our understanding of the molecular mechanisms underlying muscle specific differences in response to the ICU intervention and the role played by the different triggering factors.

The sparing of masticatory muscle fiber function was coupled to an up-regulation of heat shock protein genes and down-regulation of myostatin are suggested to be key factors in the relative sparing of masticatory muscles. Up-regulation of chemokine activity genes and down-regulation of heat shock protein genes play a significant role in the limb muscle dysfunction associated with sepsis. The effects of corticosteroids in the development of limb muscle weakness reveals up-regulation of kinase activity and transcriptional regulation genes and the down-regulation of heat shock protein, sarcomeric, cytoskeletal and oxidative stress responsive genes. In contrast to limb and craniofacial muscles, the respiratory diaphragm muscle responded differently to the different triggering factors. MV itself appears to play a major role for the diaphragm muscle dysfunction. By targeting these genes, future experiments can give an insight into the development of innovative treatments expected at protecting muscle mass and function in critically ill ICU patients.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2012. , s. 66
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 812
Emneord [en]
acute quadriplegic myopathy, gene expression, myosin, heat shock proteins, mechanical ventilation, myostatin, sepsis, corticosteroids, diaphragm
HSV kategori
Forskningsprogram
Klinisk neurofysiologi
Identifikatorer
URN: urn:nbn:se:uu:diva-180374ISBN: 978-91-554-8469-9 (tryckt)OAI: oai:DiVA.org:uu-180374DiVA, id: diva2:549855
Disputas
2012-10-24, Hedstrandsalen, Ingang 70, bv Akademiska Sukhuset, Uppsala, 13:15 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2012-10-03 Laget: 2012-09-05 Sist oppdatert: 2018-01-12bibliografisk kontrollert
Delarbeid
1. Mechanisms underlying the sparing of masticatory versus limb muscle function in an experimental critical illness model
Åpne denne publikasjonen i ny fane eller vindu >>Mechanisms underlying the sparing of masticatory versus limb muscle function in an experimental critical illness model
Vise andre…
2011 (engelsk)Inngår i: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 43, nr 24, s. 1334-1350Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Acute quadriplegic myopathy (AQM) is a common debilitating acquired disorder in critically ill intensive care unit (ICU) patients which is characterized by tetraplegia/generalized weakness of limb and trunk muscles. Masticatory muscles, on the other hand, are typically spared or less affected, yet the mechanisms underlying this striking muscle-specific difference remain unknown. This study aims to evaluate physiological parameters and the gene expression profiles of masticatory and limb muscles exposed to factors suggested to trigger AQM, such as mechanical ventilation, immobilization, neuromuscular blocking agents (NMBA), corticosteroids (CS) and sepsis for five days by using a unique porcine model mimicking the ICU conditions. Single muscle fiber cross-sectional area and force-generating capacity, i.e., maximum force normalized to fiber cross-sectional area (specific force), revealed maintained masseter single muscle fiber cross-sectional area and specific-force after five days exposure to all triggering factors. This is in sharp contrast to observations in limb and trunk muscles, showing a dramatic decline in specific force in response to five days exposure to the triggering factors. Significant differences in gene expression were observed between craniofacial and limb muscles, indicating a highly complex and muscle specific response involving transcription and growth factors, heat shock proteins, matrix metalloproteinase inhibitor, oxidative stress responsive elements and sarcomeric proteins underlying the relative sparing of cranial versus spinal nerve innervated muscles during exposure to the ICU intervention.

HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-164317 (URN)10.1152/physiolgenomics.00116.2011 (DOI)000298403600002 ()22010006 (PubMedID)
Tilgjengelig fra: 2011-12-19 Laget: 2011-12-19 Sist oppdatert: 2017-12-08bibliografisk kontrollert
2. The role of sepsis in the development of limb muscle weakness in a porcine intensive care unit model
Åpne denne publikasjonen i ny fane eller vindu >>The role of sepsis in the development of limb muscle weakness in a porcine intensive care unit model
Vise andre…
2012 (engelsk)Inngår i: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 44, nr 18, s. 865-877Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Severe muscle wasting and loss of muscle function in critically ill mechanically ventilated intensive care unit (ICU) patients have significant negative consequences on their recovery and rehabilitation that persist long after their hospital discharge; moreover the underlying mechanisms are unclear. Mechanical ventilation (MV) and immobilization-induced modifications play an important role in these consequences, including endotoxin induced sepsis. The present study aims to investigate how sepsis aggravates ventilator and immobilization-related limb muscle dysfunction. Hence, biceps femoris muscle gene expression was investigated in pigs exposed to ICU intervention, i.e., immobilization, sedation, and MV, alone or in combination with sepsis for five days. In previous studies, we have shown that ICU intervention alone or in combination with sepsis did not affect muscle fiber size on day 5, but a significant decrease was observed in single fiber maximal force normalized to cross-sectional area (specific force) when sepsis was added to the ICU intervention. According to microarray data, the addition of sepsis to the ICU intervention induced a deregulation of more than 500 genes, such as an increased expression of genes involved in chemokine activity, kinase activity and transcriptional regulation. Genes involved in the regulation of the oxidative stress response, cytoskeletal/sarcomeric and heat shock proteins were on the other hand down-regulated when sepsis was added to the ICU intervention. Thus, sepsis has a significant negative effect on muscle function in critically ill ICU patients and chemokine activity and heat shock protein genes are forwarded to play an instrumental role in this specific muscle wasting condition.

Emneord
Sepsis, porcine, muscle wasting, intensive care
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-180380 (URN)10.1152/physiolgenomics.00031.2012 (DOI)000309109100001 ()
Tilgjengelig fra: 2012-09-05 Laget: 2012-09-05 Sist oppdatert: 2017-12-07bibliografisk kontrollert
3. Effects of corticosteroids in the development of limb muscle weakness in a porcine intensive care unit model
Åpne denne publikasjonen i ny fane eller vindu >>Effects of corticosteroids in the development of limb muscle weakness in a porcine intensive care unit model
Vise andre…
2013 (engelsk)Inngår i: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 45, nr 8, s. 312-320Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Severe muscle wasting is a debilitating condition in critically ill intensive care unit (ICU) patients, characterized by general muscle weakness and dysfunction, resulting in a prolonged mobilization, delayed weaning from the ventilator and a decreased quality of life post-ICU. The mechanisms underlying limbmuscle weakness in ICU patients are complex and involve the impact of primary disease, but also factors common to critically ill ICU patients such as sepsis, mechanical ventilation (MV), immobilization and systemic administration of corticosteroids (CS).  These factors may have additive negative effects on skeletal muscle structure and function, but their respective role alone remain unknown. The primary aim of this study was to examine how CS administration potentiates ventilator and immobilization-related limb muscle dysfunction at the gene level. Comparing biceps femoris gene expression in pigs exposed to MV and CS for five days with only MV pigs for the same duration of time showed a distinct deregulation of 186 genes using microarray. Surprisingly, the decreased force-generation capacity at the single muscle fiber reported in response to the addition of CS administration in mechanically ventilated and immobilized pigs was not associated with an additional up-regulation of proteolytic pathways. On the other hand, an altered expression of genes regulating kinase activity, cell cycle, transcription, channel regulation, oxidative stress response , cytoskeletal, sarcomeric and heat shock protein as well as protein synthesis at the translational level appear to play an additive deleterious role for the  limb muscle weakness in immobilized ICU patients.

 

HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-180375 (URN)10.1152/physiolgenomics.00123.2012 (DOI)000317662000002 ()23429211 (PubMedID)
Tilgjengelig fra: 2012-09-05 Laget: 2012-09-05 Sist oppdatert: 2017-12-07bibliografisk kontrollert
4. Diaphragm muscle weakness in an experimental porcine intensive care unit model
Åpne denne publikasjonen i ny fane eller vindu >>Diaphragm muscle weakness in an experimental porcine intensive care unit model
Vise andre…
2011 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, nr 6, artikkel-id e20558Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

In critically ill patients, mechanisms underlying diaphragm muscle remodeling and resultant dysfunction contributing to weaning failure remain unclear. Ventilator-induced modifications as well as sepsis and administration of pharmacological agents such as corticosteroids and neuromuscular blocking agents may be involved. Thus, the objective of the present study was to examine how sepsis, systemic corticosteroid treatment (CS) and neuromuscular blocking agent administration (NMBA) aggravate ventilator-related diaphragm cell and molecular dysfunction in the intensive care unit. Piglets were exposed to different combinations of mechanical ventilation and sedation, endotoxin-induced sepsis, CS and NMBA for five days and compared with sham-operated control animals. On day 5, diaphragm muscle fibre structure (myosin heavy chain isoform proportion, cross-sectional area and contractile protein content) did not differ from controls in any of the mechanically ventilated animals. However, a decrease in single fibre maximal force normalized to cross-sectional area (specific force) was observed in all experimental piglets. Therefore, exposure to mechanical ventilation and sedation for five days has a key negative impact on diaphragm contractile function despite a preservation of muscle structure. Post-translational modifications of contractile proteins are forwarded as one probable underlying mechanism. Unexpectedly, sepsis, CS or NMBA have no significant additive effects, suggesting that mechanical ventilation and sedation are the triggering factors leading to diaphragm weakness in the intensive care unit.

HSV kategori
Forskningsprogram
Klinisk neurofysiologi
Identifikatorer
urn:nbn:se:uu:diva-155622 (URN)10.1371/journal.pone.0020558 (DOI)000291730000014 ()21698290 (PubMedID)
Tilgjengelig fra: 2011-06-27 Laget: 2011-06-27 Sist oppdatert: 2018-01-12bibliografisk kontrollert

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