2. Academic Validation
  3. The chaperone co-inducer BGP-15 alleviates ventilation-induced diaphragm dysfunction

The chaperone co-inducer BGP-15 alleviates ventilation-induced diaphragm dysfunction

  • Sci Transl Med. 2016 Aug 3;8(350):350ra103. doi: 10.1126/scitranslmed.aaf7099.
Heba Salah 1,  Meishan Li 2,  Nicola Cacciani 2,  Stefano Gastaldello 2,  Hannah Ogilvie 2,  Hazem Akkad 2,  Arvind Venkat Namuduri 2,  Valeria Morbidoni 3,  Konstantin A Artemenko 4,  Gabor Balogh 5,  Vicente Martinez-Redondo 2,  Paulo Jannig 2,  Yvette Hedström 2,  Barry Dworkin 6,  Jonas Bergquist 7,  Jorge Ruas 2,  Laszlo Vigh 5,  Leonardo Salviati 3,  Lars Larsson 8
Affiliations

Affiliations

  • 1 Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm SE-177 77, Sweden. Department of Neuroscience, Clinical Neurophysiology, Uppsala University, Uppsala 75124, Sweden.
  • 2 Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm SE-177 77, Sweden.
  • 3 Clinical Genetics Unit, Department of Women's and Children's Health, University of Padova, Padova 35128, Italy.
  • 4 Analytical Chemistry, Department of Chemistry-Biomedical Centre and Science for Life Laboratory (SciLifeLab), Uppsala University, Uppsala 75124, Sweden.
  • 5 Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Szeged H-6726, Hungary.
  • 6 Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm SE-177 77, Sweden. Department of Neuroscience, Pennsylvania State University, Hershey, PA 17033, USA.
  • 7 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.
  • 8 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.
PMID: 27488897 DOI: 10.1126/scitranslmed.aaf7099
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.

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