Prolonged controlled mechanical ventilation in humans triggers myofibrillar contractile dysfunction and myofilament protein loss in the diaphragm

Author(s):Show less -

Hussain, Sabah N. A. ^{[1, 2, 3, 4, 5]} ; Cornachione, Anabelle S. ^[6] ; Guichon, Celine ^{[1, 4]} ; Al Khunaizi, Auday ^{[1, 4]} ; Leite, Felipe de Souza ^[7] ; Petrof, Basil J. ^{[1, 2, 3]} ; Mofarrahi, Mahroo ^{[1, 4]} ; Moroz, Nikolay ^{[1, 4]} ; de Varennes, Benoit ^[8] ; Goldberg, Peter ^{[1, 2, 3, 4]} ; Rassier, Dilson E. ^{[9, 10, 11]}

Affiliation:Show less -

^[1] McGill Univ, Meakins Christie Labs, Montreal, PQ H2W 1S4 - Canada

^[2] McGill Univ, Div Resp, Montreal, PQ H2W 1S4 - Canada

^[3] McGill Univ, Program Translat Res Resp Dis, Ctr Hlth, Res Inst, Montreal, PQ H2W 1S4 - Canada

^[4] McGill Univ, Crit Care Div, Montreal, PQ H2W 1S4 - Canada

^[5] McGill Univ, Ctr Hlth, Dept Crit Care, Res Inst, Montreal, PQ H2W 1S4 - Canada

^[6] Univ Sao Paulo, Ribeirao Preto Sch Med, Dept Pathol, BR-14049 Ribeirao Preto - Brazil

^[7] McGill Univ, Dept Kinesiol, 475 Pine Ave West, Montreal, PQ H2W 1S4 - Canada

^[8] McGill Univ, Dept Surg, Fac Med, Div Cardiac Surg, Montreal, PQ H2W 1S4 - Canada

^[9] McGill Univ, Dept Kinesiol & Phys Educ, Montreal, PQ H2W 1S4 - Canada

^[10] McGill Univ, Dept Physiol, Montreal, PQ H2W 1S4 - Canada

^[11] McGill Univ, Dept Phys, Montreal, PQ H2W 1S4 - Canada

• Document type: Journal article
• Source: THORAX; v. 71, n. 5, p. 436-445, MAY 2016.
• Web of Science Citations: 18

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 (K-act), force redevelopment after a shortening protocol (K-tr) and relaxation (K-rel) 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, K-act, K-tr and K-rel. 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 alpha-actin, alpha-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. (AU)

• FAPESP's process: 13/07104-6 - Effects of eccentric exercise in skeletal muscle rehabilitation of mdx mice after long period of training: morphological, functional and molecular evaluations
• Grantee: Anabelle Silva Cornachione
• Support type: Research Grants - Young Investigators Grants