In healthy humans, ventilation is propelled by the rhythmic contraction of the diaphragm, the main muscle of inspiration. In contrast, in patients admitted to the intensive care unit, ventilation is carried out by a machine - to facilitate oxygen uptake in the lungs - and the diaphragm is inactive. However, mechanical ventilation is clearly a two-edged sword: recent studies suggest that during mechanical ventilation the diaphragm rapidly weakens. Thus, prolonged mechanical ventilation may be required because of diaphragm weakness caused by the mechanical ventilation itself. This so-called weaning failure is frequently encountered in ICU patients and contributes to mortality. My laboratory aims to unravel the complex pathophysiology of diaphragm weakness in critically ill patients. We particularly focus on the putative role of titin, a giant mechanosensor protein. For our studies we make use of genetically engineered mouse models and unique diaphragm biopsies of critically ill patients.