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Aare, S., Radell, P., Eriksson, L., Akkad, H., Chen, Y.-W., Hoffman, E. & Lars, L. (2013). Effects of corticosteroids in the development of limb muscle weakness in a porcine intensive care unit model. Physiological Genomics, 45(8), 312-320
Öppna denna publikation i ny flik eller fönster >>Effects of corticosteroids in the development of limb muscle weakness in a porcine intensive care unit model
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2013 (Engelska)Ingår i: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 45, nr 8, s. 312-320Artikel i tidskrift (Refereegranskat) 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.

 

Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-180375 (URN)10.1152/physiolgenomics.00123.2012 (DOI)000317662000002 ()23429211 (PubMedID)
Tillgänglig från: 2012-09-05 Skapad: 2012-09-05 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
Banduseela, V., Chen, Y.-w., Göransson Kultima, H., Norman, H., Aare, S., Radell, P., . . . Larsson, L. (2013). Impaired autophagy, chaperone expression, and protein synthesis in response to critical illness interventions in porcine skeletal muscle. Physiological Genomics, 45(12), 477-486
Öppna denna publikation i ny flik eller fönster >>Impaired autophagy, chaperone expression, and protein synthesis in response to critical illness interventions in porcine skeletal muscle
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2013 (Engelska)Ingår i: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 45, nr 12, s. 477-486Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Critical illness myopathy (CIM) is characterized by a preferential loss of the motor protein myosin, muscle wasting, and impaired muscle function in critically ill intensive care unit (ICU) patients. CIM is associated with severe morbidity and mortality and has a significant negative socioeconomic effect. Neuromuscular blocking agents, corticosteroids, sepsis, mechanical ventilation, and immobilization have been implicated as important risk factors, but the causal relationship between CIM and the risk factors has not been established. A porcine ICU model has been used to determine the immediate molecular and cellular cascades that may contribute to the pathogenesis prior to myosin loss and extensive muscle wasting. Expression profiles have been compared between pigs exposed to the ICU interventions, i.e., mechanically ventilated, sedated, and immobilized for 5 days, with pigs exposed to critical illness interventions, i.e., neuromuscular blocking agents, corticosteroids, and induced sepsis in addition to the ICU interventions for 5 days. Impaired autophagy as well as impaired chaperone expression and protein synthesis were observed in the skeletal muscle in response to critical illness interventions. A novel finding in this study is impaired core autophagy machinery in response to critical illness interventions, which when in concert with downregulated chaperone expression and protein synthesis may collectively affect the proteostasis in skeletal muscle and may exacerbate the disease progression in CIM.

Nyckelord
intensive care unit; porcine ICU model; autophagy; chaperones; protein synthesis; skeletal muscle; critical illness myopathy and skeletal muscle proteostasis
Nationell ämneskategori
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
Forskningsämne
Medicinsk cellbiologi
Identifikatorer
urn:nbn:se:uu:diva-183955 (URN)10.1152/physiolgenomics.00141.2012 (DOI)000320507100003 ()
Tillgänglig från: 2012-11-06 Skapad: 2012-11-06 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
Aare, S. R. (2012). Intensive Care Unit Muscle Wasting: Skeletal Muscle Phenotype and Underlying Molecular Mechanisms. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Öppna denna publikation i ny flik eller fönster >>Intensive Care Unit Muscle Wasting: Skeletal Muscle Phenotype and Underlying Molecular Mechanisms
2012 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2012. s. 66
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 812
Nyckelord
acute quadriplegic myopathy, gene expression, myosin, heat shock proteins, mechanical ventilation, myostatin, sepsis, corticosteroids, diaphragm
Nationell ämneskategori
Medicin och hälsovetenskap Neurovetenskaper
Forskningsämne
Klinisk neurofysiologi
Identifikatorer
urn:nbn:se:uu:diva-180374 (URN)978-91-554-8469-9 (ISBN)
Disputation
2012-10-24, Hedstrandsalen, Ingang 70, bv Akademiska Sukhuset, Uppsala, 13:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2012-10-03 Skapad: 2012-09-05 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
Aare, S., Radell, P., Eriksson, L., Chen, Y.-W., Hoffman, E. P. & Larsson, L. (2012). The role of sepsis in the development of limb muscle weakness in a porcine intensive care unit model. Physiological Genomics, 44(18), 865-877
Öppna denna publikation i ny flik eller fönster >>The role of sepsis in the development of limb muscle weakness in a porcine intensive care unit model
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2012 (Engelska)Ingår i: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 44, nr 18, s. 865-877Artikel i tidskrift (Refereegranskat) 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.

Nyckelord
Sepsis, porcine, muscle wasting, intensive care
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-180380 (URN)10.1152/physiolgenomics.00031.2012 (DOI)000309109100001 ()
Tillgänglig från: 2012-09-05 Skapad: 2012-09-05 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
Ochala, J., Renaud, G., Llano Diez, M., Banduseela, V. C., Aare, S., Ahlbeck, K., . . . Larsson, L. (2011). Diaphragm muscle weakness in an experimental porcine intensive care unit model. PLOS ONE, 6(6), Article ID e20558.
Öppna denna publikation i ny flik eller fönster >>Diaphragm muscle weakness in an experimental porcine intensive care unit model
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2011 (Engelska)Ingår i: PLOS ONE, E-ISSN 1932-6203, Vol. 6, nr 6, artikel-id e20558Artikel i tidskrift (Refereegranskat) 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.

Nationell ämneskategori
Fysiologi
Forskningsämne
Klinisk neurofysiologi
Identifikatorer
urn:nbn:se:uu:diva-155622 (URN)10.1371/journal.pone.0020558 (DOI)000291730000014 ()21698290 (PubMedID)
Tillgänglig från: 2011-06-27 Skapad: 2011-06-27 Senast uppdaterad: 2021-06-14Bibliografiskt granskad
Aare, S., Ochala, J., Norman, H. S., Radell, P., Eriksson, L. I., Göransson, H., . . . Larsson, L. (2011). Mechanisms underlying the sparing of masticatory versus limb muscle function in an experimental critical illness model. Physiological Genomics, 43(24), 1334-1350
Öppna denna publikation i ny flik eller fönster >>Mechanisms underlying the sparing of masticatory versus limb muscle function in an experimental critical illness model
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2011 (Engelska)Ingår i: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 43, nr 24, s. 1334-1350Artikel i tidskrift (Refereegranskat) 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.

Nationell ämneskategori
Neurologi
Identifikatorer
urn:nbn:se:uu:diva-164317 (URN)10.1152/physiolgenomics.00116.2011 (DOI)000298403600002 ()22010006 (PubMedID)
Tillgänglig från: 2011-12-19 Skapad: 2011-12-19 Senast uppdaterad: 2017-12-08Bibliografiskt granskad
Ochala, J., Gustafson, A.-M., Diez, M. L., Renaud, G., Li, M., Aare, S., . . . Larsson, L. (2011). Preferential skeletal muscle myosin loss in response to mechanical silencing in a novel rat intensive care unit model: underlying mechanisms. Journal of Physiology, 589(8), 2007-2026
Öppna denna publikation i ny flik eller fönster >>Preferential skeletal muscle myosin loss in response to mechanical silencing in a novel rat intensive care unit model: underlying mechanisms
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2011 (Engelska)Ingår i: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 589, nr 8, s. 2007-2026Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Non-technical summary Wasting and severely impaired function of skeletal muscle is frequently observed in critically ill intensive care unit (ICU) patients, with negative consequences for recovery and quality of life. An experimental rat ICU model has been used to study the mechanisms underlying this unique wasting condition in neuromuscularly blocked and mechanically ventilated animals at durations varying between 6 h and 2 weeks. The complete 'mechanical silencing' of skeletal muscle (removal of both weight bearing and activation) resulted in a specific myopathy frequently observed in ICU patients and characterized by a preferential loss of the motor protein myosin. A highly complex and coordinated protein synthesis and degradation system was observed in the time-resolved analyses. It is suggested the 'mechanical silencing' of skeletal muscle is a dominating factor triggering the specific myopathy associated with the ICU intervention, and strongly supporting the importance of interventions counteracting the complete unloading in ICU patients.The muscle wasting and impaired muscle function in critically ill intensive care unit (ICU) patients delay recovery from the primary disease, and have debilitating consequences that can persist for years after hospital discharge. It is likely that, in addition to pernicious effects of the primary disease, the basic life support procedures of long-term ICU treatment contribute directly to the progressive impairment of muscle function. This study aims at improving our understanding of the mechanisms underlying muscle wasting in ICU patients by using a unique experimental rat ICU model where animals are mechanically ventilated, sedated and pharmacologically paralysed for duration varying between 6 h and 14 days. Results show that the ICU intervention induces a phenotype resembling the severe muscle wasting and paralysis associated with the acute quadriplegic myopathy (AQM) observed in ICU patients, i.e. a preferential loss of myosin, transcriptional down-regulation of myosin synthesis, muscle atrophy and a dramatic decrease in muscle fibre force generation capacity. Detailed analyses of protein degradation pathways show that the ubiquitin proteasome pathway is highly involved in this process. A sequential change in localisation of muscle-specific RING finger proteins 1/2 (MuRF1/2) observed during the experimental period is suggested to play an instrumental role in both transcriptional regulation and protein degradation. We propose that, for those critically ill patients who develop AQM, complete mechanical silencing, due to pharmacological paralysis or sedation, is a critical factor underlying the preferential loss of the molecular motor protein myosin that leads to impaired muscle function or persisting paralysis.

Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-152844 (URN)10.1113/jphysiol.2010.202044 (DOI)000289527200018 ()
Tillgänglig från: 2011-05-03 Skapad: 2011-05-02 Senast uppdaterad: 2022-01-28Bibliografiskt granskad
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