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Prolonged controlled mechanical ventilation in humans triggers myofibrillar contractile dysfunction and myofilament protein loss in the diaphragm
  1. Sabah N A Hussain1,2,3,
  2. Anabelle S Cornachione4,
  3. Céline Guichon1,
  4. Auday Al Khunaizi1,
  5. Felipe de Souza Leite5,
  6. Basil J Petrof3,
  7. Mahroo Mofarrahi1,
  8. Nikolay Moroz1,
  9. Benoit de Varennes6,
  10. Peter Goldberg1,3,
  11. Dilson E Rassier7
  1. 1Meakins-Christie Laboratories and Critical Care Division, McGill University, Montréal, Québec, Canada
  2. 2Department of Critical Care, McGill University Health Centre Research Institute, Montréal, Québec, Canada
  3. 3Meakins-Christie Laboratories and Respiratory Division, McGill University, and Program for Translational Research in Respiratory Diseases, McGill University Health Centre Research Institute, Montréal, Québec, Canada
  4. 4Department of Pathology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, Brazil
  5. 5Department of Kinesiology, McGill University, Montréal, Québec, Canada
  6. 6Division of Cardiac Surgery, Department of Surgery, Faculty of Medicine, McGill University, Montréal, Québec, Canada
  7. 7Departments of Kinesiology and Physical Education, Physiology and Physics, McGill University, Montreal, Quebec, Canada
  1. Correspondence to Professor Dilson Rassier, Department of Kinesiology, McGill University, 475 Pine Ave West, Montréal, Québec, Canada H2W 1S4; dilson.rassier{at}mcgill.ca

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.

Methods and 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 (pCa2+=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.

  • Respiratory Muscles
  • Assisted Ventilation

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