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

Abstract

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.

Low-force transitions in single titin molecules reflect a memory of contractile history

“…The history-dependent mechanical behavior of titin might serve as a mechanosensor only if information is relayed towards signal-transduction pathways, which are typically cascades of molecular recognition and binding (Krüger and Linke, 2009;Linke, 2007;Ottenheijm et al, 2011;Voelkel and Linke, 2011). Conceivably, the low-force structural transitions in titin change the exposure of sites to phosphorylation and the binding of ligands.…”

“…Mechanobiological phenomena require the sensing of the local mechanical environment, the cellular and molecular mechanisms of which are not well understood. In muscle, it is hypothesized that the giant elastomeric protein titin plays an important role in the mechanosensory process (Gautel, 2010;Granzier and Labeit, 2005;Krüger and Linke, 2009;Ottenheijm et al, 2011;Voelkel and Linke, 2011). Titin (also known as connectin) forms an integrating filamentous scaffold within the striated muscle sarcomere (Funatsu et al, 1990;Gregorio et al, 1999;Maruyama, 1997;Wang, 1996;Wells, 2013).…”

“…It spans the middle and the edge of the sarcomere and is tightly bound in the Z-disk, the M-line and the thick filament. It is a linear chain of globular (immunoglobulin, Ig and fibronectin, FN) domains interrupted with unique sequences such as the unstructured PEVK domain (Gautel, 2010;Granzier and Labeit, 2005;Krüger and Linke, 2009;Labeit and Kolmerer, 1995;Ottenheijm et al, 2011;Voelkel and Linke, 2011). Alternative splicing that affects the Iband section results in tissue-specific size isoforms, which differ in the number of Ig domains and the size of the PEVK domain.…”

Titin-based stiffening of muscle fibers in Ehlers-Danlos Syndrome

“…Titin is a giant sarcomeric protein (3)(4) MDa) that spans the half-sarcomeric distance from the Z-disk to the M-band, thus forming the third sarcomeric filament, in addition to the thick (mostly myosin) and thin (mostly actin) filaments (24,29) (for schematic see Fig. 3C).…”

Ventilator-induced Diaphragm Dysfunction

“…A pressing example awaiting explanation is how muscle inactivity triggers the cellular changes associated with VIDD. A postulated candidate is titin, a long filamentous sarcomeric protein that functions as a mechanosensor by altering its signaling kinase domain activity in response to mechanical stretch 8 ; selective expression of this gene or mutation of its kinase domain would allow exploration of its role in VIDD.…”