Titin-based mechanosensing and signaling: Role in diaphragm atrophy during unloading?

The diaphragm, the main muscle of inspiration, is constantly subjected to mechanical loading. One of the very few occasions during which diaphragm loading is arrested is during controlled mechanical ventilation in the intensive care unit. Recent animal studies indicate that the diaphragm is extremely sensitive to unloading, causing rapid muscle fiber atrophy: unloading-induced diaphragm atrophy and the concomitant diaphragm weakness has been suggested to contribute to the difficulties in weaning patients from ventilatory support. Little is known about the molecular triggers that initiate the rapid unloading atrophy of the diaphragm, 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 the largest protein known to date and acts as a mechanosensor that regulates 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.