Caveolae respond to cell stretch and contribute to stretch-induced signaling

Abstract

SummaryCaveolae are invaginations of the plasma membrane that are formed by caveolins. Caveolar membranes are also enriched in cholesterol, glycosphingolipids and signaling enzymes such as Src kinase. Here we investigate the effect of cell stretch upon caveolar dynamics and signaling. Transfection of C2 myoblasts with caveolin-3-YFP led to the formation of caveolae-like membrane pits 50-100 nm in diameter. Glycosphingolipids became immobilized and tightly packed together within caveolin-rich regions of the plasma membrane. Fluorescence resonance energy transfer (FRET) was used to assess the degree of glycosphingolipid packing. Myoblasts were subjected to a brief (1 minute) stretch on an elastic substratum. Stretch caused a reduction in glycosphingolipid FRET, consistent with a reversible unfolding of caveolar pits in response to membrane tension. Cells expressing caveolin-3-YFP also displayed an enhanced stretchinduced activation of Src kinase, as assessed by immunofluorescence. Repeated stretches resulted in the trafficking and remodeling of caveolin-3-rich membrane domains and accelerated turnover of membrane glycosphingolipids. The stretch-induced unfolding of caveolae, activation of Src and redistribution of caveolin and glycosphingolipids might reflect mechanisms of the cellular adaptation to mechanical stresses.

Orientation-specific responses to sustained uniaxial stretching in focal adhesion growth and turnover

“…Thus, it is possible that inhibition of SFKs could promote rapid FA growth through the inactivation of the caveolin pathway. Indeed, mechanoregulation of the caveolin pathway has been documented (53,54). In contrast, although our immunofluorescence results indicate that FAK activity increases rapidly in FAs perpendicular to stretch, pretreatment with FAK inhibitor blocked both rapid FA growth (independent of FA orientation) and delayed FA disassembly (in perpendicular FAs), which suggests that baseline FAK activity is required for rapid FA growth in all FAs, but reaching a high threshold of FAK activity is required for the delayed FA disassembly.…”

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

“…Calcium-and sodium-permeable stretch-activated channels (SAC) respond to mechanical stimuli and various intracellular signaling cascades. In addition, membrane invaginations, i.e., caveolae, respond to cell stress and stretch-induced signaling, and many different proteins involved in cell signaling bind to caveolins, such as neural nitric oxide synthase (nNOS), G protein subunits, tyrosine kinases, small GTPases, and growth receptors (240,641). The cytokine leukemia inhibitory factor (LIF) plays an important role in muscle hypertrophy in response to mechanical loading (651).…”

Caveolae – mechanosensitive membrane invaginations linked to actin filaments

“…However, the number of caveolae does not change as a function of sarcomere length in rabbit myocardial cells (Levin and Page, 1980), raising the possibility that caveolae flattening might occur only in vivo in certain tissues. More recent studies have shown that mechanical stretching of cells or their osmotic swelling result in the flattening of about half of the caveolae (Kozera et al, 2009;Gervasio et al, 2011;Sinha et al, 2011). Caveolae flattening is also generated by an excess of stress fibers (Echarri et al, 2012), which results in an increase in membrane tension (Tamura et al, 2010;Echarri et al, 2012).…”