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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
URN: urn:nbn:se:uu:diva-303060DOI: 10.1126/scitranslmed.aaf7099ISI: 000380780000005OAI: oai:DiVA.org:uu-303060DiVA: diva2:970684
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: 2016-09-14Bibliographically approved

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