Gravity plays a central role in vertebrate development and evolution. Gravitational forces acting on mammalian tissues cause the net muscle forces required for locomotion to be higher on earth than on a body subjected to a microgravitational field. As body mass increases during development, the musculoskeleton must be able to adapt by increasing the size of its functional units. Thus mechanical forces required to do the work (mechanical energy) of locomotion must be sensed by cells and converted into chemical energy (synthesis of new tissue). Extracellular matrices (ECMs) are multicomponent tissues that transduce internal and external mechanical signals into changes in tissue structure and function through a process termed mechanochemical transduction. Under the influence of an external gravitational field, both mineralized and unmineralized vertebrate tissues exhibit internal tensile forces that serve to preserve a synthetic phenotype in the resident cell population. Application of additional external forces alters the balance between the external gravitational force and internal forces acting on resident cells leading to changes in the expression of genes and production of protein that ultimately may alter the exact structure and function of the extracellular matrix. Changes in the equilibrium between internal and external forces acting on ECMs and changes in mechanochemical transduction processes at the cellular level appear to be important mechanisms by which mammals adjust their needs to store, transmit, and dissipate energy that is required during development and for bodily movements. Mechanosensing is postulated to involve many different cellular and extracellular components. Mechanical forces cause direct stretching of protein-cell surface integrin binding sites that occur on all eukaryotic cells. Stress-induced conformational changes in the extracellular matrix may alter integrin structure and lead to activation of several secondary messenger pathways within the cell. Activation of these pathways leads to altered regulation of genes that synthesize and catabolize extracellular matrix proteins as well as to alterations in cell division. Another aspect by which mechanal signals are transduced involves deformation of gap junctions containing calcium-sensitive stretch receptors. Once activated, these channels trigger secondary messenger activation through pathways similar to those involved in integrin-dependent activation and allow cell-to-cell communications between cells with similar and different phenotypes. Another process by which mechanochemical transduction occurs is through the activation of ion channels in the cell membrane. Mechanical forces have been shown to alter cell membrane ion channel permeability associated with Ca(+2) and other ion fluxes. In addition, the application of mechanical forces to cells leads to the activation of growth factor and hormone receptors even in the absence of ligand binding. These are some of the mechanisms that have evolved in vertebrates by which cells respond to changes in external forces that lead to changes in tissue strcture and function.
"Another study reported that FFSS opens Cx43 HC on the plasma membrane in osteocytes to trigger the release of ATP by a protein-kinase-C-mediated pathway (Genetos et al., 2007). Given that mechanical forces are also known to deform the extracellular matrix, they can alter the integrin protein conformation leading to activation of secondary messenger pathways or exert their effect directly on the cell surface protein–integrin complex (Silver and Siperko, 2003). We have previously shown that FFSS increases the assembly and cell surface expression of Cx43 HC (Siller-Jackson et al., 2008). "
[Show abstract][Hide abstract] ABSTRACT: Intracellular signaling in osteocytes activated by mechanical loading is important for bone formation and remodeling. These signaling events are mediated by small modulators released from Cx43 hemichannels (HC). We have recently shown that integrin α5 senses the mechanical stimulation and induces the opening of Cx43 HC; however, the underlying mechanism is unknown. Here, we show that both Cx43 and integrin α5 interact with 14-3-3θ, and this interaction is required for the opening of Cx43 HC upon mechanical stress. Ablation of 14-3-3θ prevented the interaction between Cx43 and integrin α5, and blocked HC opening. It further decreased the transport of Cx43 and integrin α5 from the Golgi to the plasma membrane. Moreover, mechanical loading promoted the movement of Cx43 to the surface which was associated not only with an increase in 14-3-3θ levels but also its interaction with Cx43 and integrin α5. This stimulatory effect on forward transport by mechanical loading was attenuated in the absence of 14-3-3θ and majority of the Cx43 was accumulated in the Golgi. Disruption of Golgi apparatus by brefeldin A reduced the association of Cx43 and integrin α5 with 14-3-3θ, further suggesting that the interaction is likely to occur in the Golgi. Together, these results define a novel, scaffolding role of 14-3-3θ in assisting the delivery of Cx43 and integrin α5 to the plasma membrane for the formation of mechanosensitive HC in osteocytes.
"The application of forces to cell adhesion points, the focal adhesions, results in the transmission of the forces into the cells. Along the chain of force transmission, some protein conformational change takes place which in turn elicits biochemical processes (Silver and Siperko, 2003) as well as direct effects on the nucleus leading to transcription and production of proteins (Dahl et al., 2008). The major load-bearing component of such responses is again the cytoskeleton (Hoffman et al., 2011) and hence force generation and mechanotransduction are intimately linked. "
[Show abstract][Hide abstract] ABSTRACT: Many attempts have been made to understand the origin of life and biological complexity both at the experimental and theoretical levels but neither is fully explained. In an influential work, Maynard Smith and Szathmáry (1995) argued that the majority of the increase in complexity is not gradual, but it is associated with a few so-called major transitions along the way of the evolution of life. For each major transition, they identified specific mechanisms that could account for the change in complexity related to information transmission across generations. In this work, I propose that the sudden and unexpected improvement in the functionality of an organism that followed a major transition was enabled by a phase transition in the network structure associated with that function. The increase in complexity following a major transition is therefore directly linked to the emergence of a novel structure-function relation which altered the course of evolution. As a consequence, emergent phenomena arising from these network phase transitions can serve as a common organizing principle for understanding the major transitions. As specific examples, I analyze the emergence of life, the emergence of the genetic apparatus, the rise of the eukaryotic cells, the evolution of movement and mechanosensitivity, and the emergence of consciousness. Finally, I discuss the implications of network associated phase transitions to issues that bear relevance to the history, the immediate present and perhaps the future, of life.
Frontiers in Physiology 04/2012; 3:94. DOI:10.3389/fphys.2012.00094 · 3.53 Impact Factor
"In addition to its potential role in chronic pain, an important characteristic of connective tissue is its responsiveness to mechanical stimulation , . In particular, recent evidence suggests that low amplitude static (non-cyclical) stretching may have beneficial antifibrotic  and antiflammatory effects . "
[Show abstract][Hide abstract] ABSTRACT: The role played by nonspecialized connective tissues in chronic non-specific low back pain is not well understood. In a recent ultrasound study, human subjects with chronic low back pain had altered connective tissue structure compared to human subjects without low back pain, suggesting the presence of inflammation and/or fibrosis in the low back pain subjects. Mechanical input in the form of static tissue stretch has been shown in vitro and in vivo to have anti-inflammatory and anti-fibrotic effects. To better understand the pathophysiology of lumbar nonspecialized connective tissue as well as potential mechanisms underlying therapeutic effects of tissue stretch, we developed a carrageenan-induced inflammation model in the low back of a rodent. Induction of inflammation in the lumbar connective tissues resulted in altered gait, increased mechanical sensitivity of the tissues of the low back, and local macrophage infiltration. Mechanical input was then applied to this model as in vivo tissue stretch for 10 minutes twice a day for 12 days. In vivo tissue stretch mitigated the inflammation-induced changes leading to restored stride length and intrastep distance, decreased mechanical sensitivity of the back and reduced macrophage expression in the nonspecialized connective tissues of the low back. This study highlights the need for further investigation into the contribution of connective tissue to low back pain and the need for a better understanding of how interventions involving mechanical stretch could provide maximal therapeutic benefit. This tissue stretch research is relevant to body-based treatments such as yoga or massage, and to some stretch techniques used with physical therapy.
PLoS ONE 01/2012; 7(1):e29831. DOI:10.1371/journal.pone.0029831 · 3.23 Impact Factor
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