title: Prolonged controlled mechanical ventilation in humans triggers myofibrillar contractile dysfunction and myofilament protein loss in the diaphragm.
abstract: BACKGROUND
  Prolonged controlled mechanical ventilation (CMV) in humans and experimental animals results in diaphragm fibre atrophy and injury. In animals, prolonged CMV also triggers significant declines in diaphragm myofibril contractility. In humans, the impact of prolonged CMV on myofibril contractility remains unknown. The objective of this study was to evaluate the effects of prolonged CMV on active and passive human diaphragm myofibrillar force generation and myofilament protein levels.
  
  
  RESULTS
  Diaphragm biopsies were obtained from 13 subjects undergoing cardiac surgery (control group) and 12 brain-dead organ donors (CMV group). Subjects in each group had been mechanically ventilated for 2-4 and 12-74 h, respectively. Specific force generation of diaphragm myofibrils was measured with atomic force cantilevers. Rates of force development (Kact), force redevelopment after a shortening protocol (Ktr) and relaxation (Krel) in fully activated myofibrils (pCa(2+)=4.5) were calculated to assess myosin cross-bridge kinetics. Myofilament protein levels were measured with immunoblotting and specific antibodies. Prolonged CMV significantly decreased active and passive diaphragm myofibrillar force generation, Kact, Ktr and Krel. Myosin heavy chain (slow), troponin-C, troponin-I, troponin-T, tropomyosin and titin protein levels significantly decreased in response to prolonged CMV, but no effects on α-actin, α-actinin or nebulin levels were observed.
  
  
  CONCLUSIONS
  Prolonged CMV in humans triggers significant decreases in active and passive diaphragm myofibrillar force generation. This response is mediated, in part, by impaired myosin cross-bridge kinetics and decreased myofibrillar protein levels.
authors.affiliation: Meakins-Christie Laboratories and Critical Care Division, McGill University, Montréal, Québec, Canada Department of Critical Care, McGill University Health Centre Research Institute, Montréal, Québec, Canada Meakins-Christie Laboratories and Respiratory Division, McGill University, and Program for Translational Research in Respiratory Diseases, McGill University Health Centre Research Institute, Montréal, Québec, Canada.
authors.forename: Sabah N A
authors.initials: SN
authors.lastname: Hussain
authors.affiliation: Department of Pathology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Anabelle S
authors.initials: AS
authors.lastname: Cornachione
authors.affiliation: Meakins-Christie Laboratories and Critical Care Division, McGill University, Montréal, Québec, Canada.
authors.forename: Céline
authors.initials: C
authors.lastname: Guichon
authors.affiliation: Meakins-Christie Laboratories and Critical Care Division, McGill University, Montréal, Québec, Canada.
authors.forename: Auday
authors.initials: A
authors.lastname: Al Khunaizi
authors.affiliation: Department of Kinesiology, McGill University, Montréal, Québec, Canada.
authors.forename: Felipe de Souza
authors.initials: Fde S
authors.lastname: Leite
authors.affiliation: Meakins-Christie Laboratories and Respiratory Division, McGill University, and Program for Translational Research in Respiratory Diseases, McGill University Health Centre Research Institute, Montréal, Québec, Canada.
authors.forename: Basil J
authors.initials: BJ
authors.lastname: Petrof
authors.affiliation: Meakins-Christie Laboratories and Critical Care Division, McGill University, Montréal, Québec, Canada.
authors.forename: Mahroo
authors.initials: M
authors.lastname: Mofarrahi
authors.affiliation: Meakins-Christie Laboratories and Critical Care Division, McGill University, Montréal, Québec, Canada.
authors.forename: Nikolay
authors.initials: N
authors.lastname: Moroz
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, Faculty of Medicine, McGill University, Montréal, Québec, Canada.
authors.forename: Benoit
authors.initials: B
authors.lastname: de Varennes
authors.affiliation: Meakins-Christie Laboratories and Critical Care Division, McGill University, Montréal, Québec, Canada Meakins-Christie Laboratories and Respiratory Division, McGill University, and Program for Translational Research in Respiratory Diseases, McGill University Health Centre Research Institute, Montréal, Québec, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Goldberg
authors.affiliation: Departments of Kinesiology and Physical Education, Physiology and Physics, McGill University, Montreal, Quebec, Canada.
authors.forename: Dilson E
authors.initials: DE
authors.lastname: Rassier
mesh_terms: D000185:Actinin / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D016022:Case-Control Studies; D064211:Connectin / Q000378:metabolism; D003964:Diaphragm / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D006331:Heart Diseases / Q000601:surgery; D006801:Humans; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction; D009124:Muscle Proteins / Q000378:metabolism; D009133:Muscular Atrophy / Q000378:metabolism; D009210:Myofibrils / Q000378:metabolism* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000378:metabolism; D012121:Respiration, Artificial / Q000009:adverse effects*; D012307:Risk Factors; D013997:Time Factors; D014019:Tissue Donors; D014335:Tropomyosin / Q000378:metabolism; D019209:Troponin C / Q000378:metabolism; D019210:Troponin I / Q000378:metabolism; D020107:Troponin T / Q000378:metabolism
chemical_list: D000199:Actins; D064211:Connectin; D009124:Muscle Proteins; D014335:Tropomyosin; D019209:Troponin C; D019210:Troponin I; D020107:Troponin T; C035620:nebulin; D000185:Actinin; D018995:Myosin Heavy Chains
keywords: Assisted Ventilation; Respiratory Muscles