title: The chaperone co-inducer BGP-15 alleviates ventilation-induced diaphragm dysfunction.
abstract: 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 posttranslational 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.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm SE-177 77, Sweden. Department of Neuroscience, Clinical Neurophysiology, Uppsala University, Uppsala 75124, Sweden.
authors.forename: Heba
authors.initials: H
authors.lastname: Salah
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm SE-177 77, Sweden.
authors.forename: Meishan
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm SE-177 77, Sweden.
authors.forename: Nicola
authors.initials: N
authors.lastname: Cacciani
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm SE-177 77, Sweden.
authors.forename: Stefano
authors.initials: S
authors.lastname: Gastaldello
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm SE-177 77, Sweden.
authors.forename: Hannah
authors.initials: H
authors.lastname: Ogilvie
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm SE-177 77, Sweden.
authors.forename: Hazem
authors.initials: H
authors.lastname: Akkad
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm SE-177 77, Sweden.
authors.forename: Arvind Venkat
authors.initials: AV
authors.lastname: Namuduri
authors.affiliation: Clinical Genetics Unit, Department of Women's and Children's Health, University of Padova, Padova 35128, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Morbidoni
authors.affiliation: Analytical Chemistry, Department of Chemistry-Biomedical Centre and Science for Life Laboratory (SciLifeLab), Uppsala University, Uppsala 75124, Sweden.
authors.forename: Konstantin A
authors.initials: KA
authors.lastname: Artemenko
authors.affiliation: Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Szeged H-6726, Hungary.
authors.forename: Gabor
authors.initials: G
authors.lastname: Balogh
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm SE-177 77, Sweden.
authors.forename: Vicente
authors.initials: V
authors.lastname: Martinez-Redondo
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm SE-177 77, Sweden.
authors.forename: Paulo
authors.initials: P
authors.lastname: Jannig
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm SE-177 77, Sweden.
authors.forename: Yvette
authors.initials: Y
authors.lastname: Hedström
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm SE-177 77, Sweden. Department of Neuroscience, Pennsylvania State University, Hershey, PA 17033, USA.
authors.forename: Barry
authors.initials: B
authors.lastname: Dworkin
authors.affiliation: Analytical Chemistry, Department of Chemistry-Biomedical Centre and Science for Life Laboratory (SciLifeLab), Uppsala University, Uppsala 75124, Sweden. Department of Pathology, School of Medicine, University of Utah, Salt Lake City, UT 84112, USA. Precision Medicine, Binzhou Medical University, Yantai City, Shandong 264003, China.
authors.forename: Jonas
authors.initials: J
authors.lastname: Bergquist
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm SE-177 77, Sweden.
authors.forename: Jorge
authors.initials: J
authors.lastname: Ruas
authors.affiliation: Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Szeged H-6726, Hungary.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Vigh
authors.affiliation: Clinical Genetics Unit, Department of Women's and Children's Health, University of Padova, Padova 35128, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salviati
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm SE-177 77, Sweden. Department of Biobehavioral Health, Pennsylvania State University, University Park, PA 16802, USA. Department of Clinical Neuroscience, Clinical Neurophysiology, Karolinska Institutet, Stockholm SE-177 77, Sweden. lars.larsson@ki.se.
authors.forename: Lars
authors.initials: L
authors.lastname: Larsson
mesh_terms: D000818:Animals; D003964:Diaphragm / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D005260:Female; D007362:Intensive Care Units; D013058:Mass Spectrometry; D046529:Microscopy, Electron, Transmission; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D010091:Oximes / Q000627:therapeutic use*; D010880:Piperidines / Q000627:therapeutic use*; D040901:Proteomics; D051381:Rats; D012121:Respiration, Artificial / Q000009:adverse effects*
chemical_list: D010091:Oximes; D010880:Piperidines; C405586:BGP 15