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Does chaperone co-inducer BGP-15 mitigate the contractile dysfunction of the soleus muscle in a rat ICU model?
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi. uppsala university.
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Anestesi och intensivvård
Identifikatorer
URN: urn:nbn:se:uu:diva-328594OAI: oai:DiVA.org:uu-328594DiVA, id: diva2:1136361
Tillgänglig från: 2017-08-28 Skapad: 2017-08-28 Senast uppdaterad: 2017-08-31
Ingår i avhandling
1. Muscle Wasting in a Rat ICU Model: Underlying Mechanisms and Specific Intervention Strategies
Öppna denna publikation i ny flik eller fönster >>Muscle Wasting in a Rat ICU Model: Underlying Mechanisms and Specific Intervention Strategies
2017 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Critical care has undergone several developments in the recent years leading to improved survival. However, acquired muscle weakness in the intensive care unit (ICU) is an important complication that affects severely ill patients and can prolong their ICU stay. Critical illness myopathy (CIM) is the progressive decline in the function and mass of the limb muscles in response to exposure to the ICU condition, while ventilator-induced diaphragm dysfunction (VIDD) is the time dependent decrease in the diaphragm function after the initiation of mechanical ventilation. Since the complete underlying mechanisms for CIM and VIDD are not completely understood, there is a compelling need for research on the mechanisms of CIM and VIDD to develop intervention strategies targeting these mechanisms. The aim of this thesis was to investigate the effects of several intervention strategies and rehabilitation programs on muscle wasting associated with ICU condition. Moreover, muscle specific differences in response to exposure to the ICU condition and different interventions was investigated. Hence, a rodent ICU model was used to address the mechanistic and therapeutic aspects of CIM and VIDD. The effects of heat shock protein 72 co-inducer (HSP72), BGP-15, on diaphragm and soleus for rats exposed to different durations of ICU condition was investigated. We showed that 5 and 10 days treatment with BGP-15 improved diaphragm fiber and myosin function, protected myosin from posttranslational modification, induced HSP72 and improved mitochondrial function. Moreover, BGP-15 treatment for 5 days improved soleus muscle fibers function, improved mitochondrial structure and reduced the levels of some ubiquitin ligases. In addition to BGP-15 treatment, passive mechanical loading of the limb muscles was investigated during exposure to the ICU condition. We showed that mitochondrial dynamics and mitophagy gene expression was affected by Mechanical silencing while mechanical loading counteracted these effects. Our investigation for other pathways that can be involved in muscle wasting associated with ICU condition showed that the Janus kinase 2/ Signal transducer and activator of transcription 3 (JAK2/STAT3) pathway is differentially activated in plantaris, intercostals and diaphragm. However, further studies are required with JAK2/STAT3 inhibitors to fully examine the role of this pathway in the pathogenesis of CIM and VIDD prior to translation to clinical research.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2017. s. 61
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1368
Nyckelord
BGP-15, critical illness myopathy, janus kinase, intensive care unit, mechanical loading, muscle wasting, signal Transducer and Activator of Transcription, ventilator-induced diaphragm dysfunction
Nationell ämneskategori
Anestesi och intensivvård Klinisk medicin
Forskningsämne
Anestesiologi och intensivvård; Klinisk neurofysiologi
Identifikatorer
urn:nbn:se:uu:diva-328596 (URN)978-91-513-0061-0 (ISBN)
Disputation
2017-10-23, Seminarierum klinisk neurofysiologi, Ing 85, Akademiska sjukhuset, Uppsala, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2017-09-29 Skapad: 2017-08-31 Senast uppdaterad: 2017-10-17

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