The chaperone co-inducer BGP-15 alleviates ventilation-induced diaphragm dysfunction
2016 (English)In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 8, no 350, 350ra103Article in journal (Refereed) Published
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
Cell and Molecular Biology
IdentifiersURN: urn:nbn:se:uu:diva-303060DOI: 10.1126/scitranslmed.aaf7099ISI: 000380780000005OAI: oai:DiVA.org:uu-303060DiVA: diva2:970684
FunderThe 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