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The chaperone co-inducer BGP-15 alleviates ventilation-induced diaphragm dysfunction
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology. Karolinska Inst, Dept Physiol & Pharmacol, SE-17777 Stockholm, Sweden..
Karolinska Inst, Dept Physiol & Pharmacol, SE-17777 Stockholm, Sweden..
Karolinska Inst, Dept Physiol & Pharmacol, SE-17777 Stockholm, Sweden..
Karolinska Inst, Dept Physiol & Pharmacol, SE-17777 Stockholm, Sweden..
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2016 (English)In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 8, no 350, 350ra103Article in journal (Refereed) Published
Abstract [en]

Ventilation-induced diaphragm dysfunction (VIDD) is a marked decline in diaphragm function in response to mechanical ventilation, which has negative consequences for individual patients' quality of life and for the health care system, but specific treatment strategies are still lacking. We used an experimental intensive care unit (ICU) model, allowing time-resolved studies of diaphragm structure and function in response to long-term mechanical ventilation and the effects of a pharmacological intervention (the chaperone co-inducer BGP-15). The marked loss of diaphragm muscle fiber function in response to mechanical ventilation was caused by post-translational modifications (PTMs) of myosin. In a rat model, 10 days of BGP-15 treatment greatly improved diaphragm muscle fiber function (by about 100%), although it did not reverse diaphragm atrophy. The treatment also provided protection from myosin PTMs associated with HSP72 induction and PARP-1 inhibition, resulting in improvement of mitochondrial function and content. Thus, BGP-15 may offer an intervention strategy for reducing VIDD in mechanically ventilated ICU patients.

Place, publisher, year, edition, pages
2016. Vol. 8, no 350, 350ra103
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-303060DOI: 10.1126/scitranslmed.aaf7099ISI: 000380780000005OAI: oai:DiVA.org:uu-303060DiVA: diva2:970684
Funder
The Swedish Foundation for International Cooperation in Research and Higher Education (STINT)Swedish Research Council, 8651; 4423; 4870; 3074EU, European Research Council, CT-223756; COST CM1001The Karolinska Institutet's Research FoundationStockholm County CouncilNovo Nordisk, 100193
Available from: 2016-09-14 Created: 2016-09-14 Last updated: 2017-08-31Bibliographically approved
In thesis
1. Muscle Wasting in a Rat ICU Model: Underlying Mechanisms and Specific Intervention Strategies
Open this publication in new window or tab >>Muscle Wasting in a Rat ICU Model: Underlying Mechanisms and Specific Intervention Strategies
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 61 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1368
Keyword
BGP-15, critical illness myopathy, janus kinase, intensive care unit, mechanical loading, muscle wasting, signal Transducer and Activator of Transcription, ventilator-induced diaphragm dysfunction
National Category
Anesthesiology and Intensive Care Clinical Medicine
Research subject
Anaesthesiology and Intensive Care; Clinical Neurophysiology
Identifiers
urn:nbn:se:uu:diva-328596 (URN)978-91-513-0061-0 (ISBN)
Public defence
2017-10-23, Seminarierum klinisk neurofysiologi, Ing 85, Akademiska sjukhuset, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2017-09-29 Created: 2017-08-31 Last updated: 2017-10-17

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