Journal
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 317, Issue 2, Pages C167-C176Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00509.2018
Keywords
diaphragm; loading; mechanical ventilation; titin
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Funding
- National Institutes of Health National Heart, Lung, and Blood Institute Grant [R01-HL-121500]
- National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01-AR-073179]
- Marie Sklodowska-Curie Actions Research and Innovation Staff Exchange Grant [MSCA-RISE-2014 645648]
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The diaphragm, the main muscle of inspiration, is constantly subjected to mechanical loading. Only during controlled mechanical ventilation, as occurs during thoracic surgery and in the intensive care unit, is mechanical loading of the diaphragm arrested. Animal studies indicate that the diaphragm is highly sensitive to unloading, causing rapid muscle fiber atrophy and contractile weakness; unloading-induced diaphragm atrophy and contractile weakness have been suggested to contribute to the difficulties in weaning patients from ventilator support. The molecular triggers that initiate the rapid unloading atrophy of the diaphragm are not well understood, although proteolytic pathways and oxidative signaling have been shown to be involved. Mechanical stress is known to play an important role in the maintenance of muscle mass. Within the muscle's sarcomere, titin is considered to play an important role in the stress-response machinery. Titin is a giant protein that acts as a mechanosensor regulating muscle protein expression in a sarcomere strain-dependent fashion. Thus titin is an attractive candidate for sensing the sudden mechanical arrest of the diaphragm when patients are mechanically ventilated, leading to changes in muscle protein expression. Here, we provide a novel perspective on how titin and its biomechanical sensing and signaling might be involved in the development of mechanical unloading-induced diaphragm weakness.
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