title: The role of calpains in ventilator-induced diaphragm atrophy.
abstract: BACKGROUND
  Controlled mechanical ventilation (CMV) is associated with diaphragm dysfunction. Dysfunction results from muscle atrophy and injury of diaphragm muscle fibers. Enhanced proteolysis and reduced protein synthesis play an important role in the development of atrophy. The current study is to evaluate the effects of the calpains inhibitor calpeptin on the development of diaphragm atrophy and activation of key enzymes of the ubiquitin-proteasome pathway in rats under CMV.
  
  
  METHODS
  Three groups of rats were studied: control animals (CON, n = 8), rats subjected to 24 h of MV (CMV, n = 8), and rats subjected to 24 h of MV after administration of the calpain inhibitor calpeptin (CMVC, n = 8). The diaphragm was analyzed for calpain activity, myosin heavy chain (MHC) content, and cross-sectional area (CSA) of diaphragmatic muscle fibers as a marker for muscle atrophy. In addition, key enzymes of the ubiquitin-proteasome pathway (MAFbx and MuRF1) were also studied.
  
  
  RESULTS
  CMV resulted in loss of both MHCfastand MHCslow. Furthermore, the CSA of diaphragmatic muscle fibers was significantly decreased after 24 h of CMV. However, calpain inhibitor calpeptin prevented loss of MHC and CSA after CMV. In addition, calpeptin prevented the increase in protein expression of calpain1 and calpain2 and reduced calpain activity as indicated by reduced generation of the calpain cleavage product αII-spectrin in the diaphragm. CMV-induced upregulation of both MAFbx and MuRF1 protein levels was attenuated by treatment with calpeptin.
  
  
  CONCLUSIONS
  The calpain inhibitor calpeptin prevents MV-induced muscle atrophy. In addition, calpeptin attenuated the expression of key proteolytic enzymes known to be involved in ventilator-induced diaphragm atrophy, including MAFbx and MuRF1.
authors.affiliation: Department of Pulmonary Diseases, Shanghai East Hospital, Tongji University, Shanghai, 200120, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Pulmonary Diseases, Radboud University Medical Centre, Postbox 9101, Nijmegen, 6500 HB, the Netherlands.
authors.forename: Hieronymus W H
authors.initials: HWH
authors.lastname: van Hees
authors.affiliation: Intensive Care Medicine, Radboud University Medical Centre, Postbox 9101, Nijmegen, 6500 HB, the Netherlands.
authors.forename: Leo
authors.initials: L
authors.lastname: Heunks
authors.affiliation: NingXia Medical University, Yinchuan, 750004, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Pulmonary Diseases, Shanghai East Hospital, Tongji University, Shanghai, 200120, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Shao
authors.affiliation: NingXia Medical University, Yinchuan, 750004, China.
authors.forename: Jiaru
authors.initials: J
authors.lastname: Huang
authors.affiliation: NingXia Medical University, Yinchuan, 750004, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.affiliation: Department of Intensive Care Unit, Shanghai East Hospital, Tongji University, Shanghai, 200120, China. m_slin@sina.com.
authors.forename: Shaolin
authors.initials: S
authors.lastname: Ma
keywords: Calpain; Calpeptin; Diaphragm atrophy; Mechanical ventilation