Sabah N A Hussain1, Anabelle S Cornachione2, Céline Guichon3, Auday Al Khunaizi3, Felipe de Souza Leite4, Basil J Petrof5, Mahroo Mofarrahi3, Nikolay Moroz3, Benoit de Varennes6, Peter Goldberg7, Dilson E Rassier8. 1. 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. 2. Department of Pathology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, Brazil. 3. Meakins-Christie Laboratories and Critical Care Division, McGill University, Montréal, Québec, Canada. 4. Department of Kinesiology, McGill University, Montréal, Québec, Canada. 5. 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. 6. Division of Cardiac Surgery, Department of Surgery, Faculty of Medicine, McGill University, Montréal, Québec, Canada. 7. 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. 8. Departments of Kinesiology and Physical Education, Physiology and Physics, McGill University, Montreal, Quebec, Canada.
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 (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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
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 (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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Authors: Robert T Mankowski; Shakeel Ahmed; Thomas Beaver; Marvin Dirain; Chul Han; Phillip Hess; Tomas Martin; Barbara K Smith; Shinichi Someya; Christiaan Leeuwenburgh; A Daniel Martin Journal: J Transl Med Date: 2016-10-26 Impact factor: 5.531
Authors: M Angela Bagni; Barbara Colombini; Marta Nocella; Claudio Pregno; Anabelle S Cornachione; Dilson E Rassier Journal: Sci Rep Date: 2019-03-14 Impact factor: 4.379