Physical constraints, such as compression, shear stress, stretching and tension, play major roles during development, tissue homeostasis, immune responses and pathologies. Cells and organelles also face mechanical forces during migration and extravasation, and investigations into how mechanical forces are translated into a wide panel of biological responses, including changes in cell morphology, membrane transport, metabolism, energy production and gene expression, is a flourishing field. Recent studies demonstrate the role of macroautophagy in the integration of physical constraints. The aim of this Review is to summarize and discuss our knowledge of the role of macroautophagy in controlling a large panel of cell responses, from morphological and metabolic changes, to inflammation and senescence, for the integration of mechanical forces. Moreover, wherever possible, we also discuss the cell surface molecules and structures that sense mechanical forces upstream of macroautophagy.

Multicellular organisms have to constantly adapt to external stimuli and modifications in their intracellular milieu. Responses that maintain homeostasis are integrated at the tissue and cellular level. Organs, tissues and cells have to face both chemical (e.g. Ca2+, amino acids, cytokines, chemokines and hormones) and physical challenges. Physical challenges can be external (e.g. radiofrequency, X-rays, UV, electric fields, radioactivity and microgravity) or internal. Among the internal physical and mechanical forces, several are tissue-dependent, such as compression in bones; tension in the muscles, lung and kidney; as well as shear stress in the blood and lymphatic circulatory systems (blood flow and lymph flow) and the kidney (urinary flow) (Janmey and Miller, 2011). Some are common to all solid tissues, such as interactions with the extracellular matrix (ECM) and intercellular adhesion (Kechagia et al., 2019; Pinheiro and Bellaϊche, 2018; van Helvert et al., 2018), while others are common to all cells, with or without persistent matrix interactions, such as organelle deformation during migration, intravasation and extravasation (Feng and Kornmann, 2018; Garcia-Arcos et al., 2019; Moreau et al., 2018). Mechanical forces are integrated by all cell types, including stem cells, to control their differentiation program (Argentati et al., 2019; Vining and Mooney, 2017). Finally, several pathological states are dependent on changes in mechanical forces. This paradigm is particularly relevant in tumor development and metastasis (Follain et al., 2020), cardiovascular diseases (Conway and Schwartz, 2013; Garoffolo and Pesce, 2019) and inflammatory diseases (Cambré et al., 2018). Additionally, pressure injury is a major risk in critically ill populations (Alderden et al., 2017).

Similar to chemical stimuli, which are recognized at the cell surface by receptors, channels and transporters, mechanical forces are in many cases detected by cell-surface sensors that can be associated with specialized membrane structures, such as cell–cell adhesion sites, focal sites and the primary cilium (Pinheiro and Bellaϊche, 2018; Ferreira et al., 2019; Spasic and Jacobs, 2017; Sun et al., 2019). Moreover, remodeling of the different cytoskeleton filaments in the cytoplasm and nucleus triggers cytoplasmic signaling and, in certain circumstances, the onset of transcriptional programs (Janota et al., 2020; Kirby and Lammerding, 2018; Mammoto et al., 2012; Uhler and Shivashankar, 2017).

Among the cytoplasmic responses to mechanical forces, recent studies have uncovered the role of macroautophagy (hereafter referred to as autophagy) in the translation of mechanical forces into biological responses (Dupont and Codogno, 2016; Hernández-Cáceres et al., 2021; Kenific et al., 2016b; King, 2012). Autophagy is one of the major degradative pathways in cells, culminating in the lysosomal compartment (see Box 1). At the basal level, autophagy controls the quality and quantity of intracellular biomass (Mizushima and Komatsu, 2011). Autophagy is also a stress-responsive catabolic process that is induced by many different physiological stimuli and pathophysiological situations, including nutrient deprivation, growth factor withdrawal, hypoxia, oxidative stress, protein accumulation and infection (Levine and Kroemer, 2019).

Box 1. Brief overview of autophagy

Autophagy requires the formation of a double-membrane-bound vacuole called the autophagosome, which selectively or non-selectively sequesters fractions of the cytoplasm to deliver them to the lysosome (Khaminets et al., 2016). Autophagy is orchestrated by ATG proteins and associated proteins during the formation and maturation of autophagosomes into autolysosomes – from the initiation, nucleation and elongation of pre-autophagosomal structures (phagophores), to closure of the autophagosome (Mizushima et al., 2011; Nakatogawa et al., 2009) (see box figure). Initiation of autophagosome biogenesis is stimulated by changes in energy status or nutrient levels, or by various stress situations (Levine and Kroemer, 2019). Autophagy induction typically depends on the inhibition of mTORC1 kinase activity, leading to activation of the ULK complex, which is composed of the serine/threonine kinase ULK1 or ULK2 (mammalian homologs of yeast Atg1; referred to collectively as ULK1/2), ATG13, a 200 kDa focal adhesion kinase family-interacting protein (FIP200, also known as RB1CC1) and ATG101 (Kawabata and Yoshimori, 2020; Nishimura and Tooze, 2020). Recent studies have shown that VAP proteins, integral proteins of the ER membrane, recruit the ULK complex to the ER (Zhao et al., 2018). ATG9 vesicles seed the growth of the autophagosome membrane. ATG9, which has a scramblase activity, interacts with ATG2, a protein that transfers phospholipids from the ER to the growing phagophore (Sawa-Makarska et al., 2020). This interaction is required for the expansion of the phagophore (Chang et al., 2021; Maeda et al., 2020).

The ULK complex activates the class III PI3K (PI3KIII) complex. The core PI3KIII complex is formed by association of the kinase VPS34 (encoded by PIK3C3 in mammals), Beclin1 (homolog of yeast Atg6), ATG14L1 and VPS15 (Kawabata and Yoshimori, 2020; Nishimura and Tooze, 2020). The production of phosphatidylinositol 3-phosphate (PI3P) allows for the recruitment of the PI3P-interacting proteins WIPI2B and ATG16L1, and then the formation of the ATG12–ATG5 ubiquitin-like conjugate. This large complex stimulates conjugation of LC3 (also known as MAP1LC3B; homolog of yeast Atg8) to phosphatidylethanolamine on the autophagic membrane. During the different forms of selective autophagy (e.g. mitophagy or aggrephagy), LC3 proteins bind to LC3-interacting region (LIR) motifs contained in cargo receptors [among others p62 (SQSTM1), NDP52 (CALCOCO2) and optineurin] (Gubas and Dikic, 2021; Johansen and Lamark, 2020). The last stage of bulk and selective autophagy is the fusion between autophagosomes and endosomes or lysosomes controlled by several factors, including small Rab GTPases and SNAREs, to induce the lysosomal degradation of autophagy cargo (Shen and Mizushima, 2014).

Autophagy is also regulated at transcriptional and epigenetic levels (Füllgrabe et al., 2014). Of note, the inhibition of mTORC1 also allows the nuclear translocation of the transcription factor TFEB, which controls lysosomal biogenesis, as well as the expression of some key autophagy genes (SQSTM1, WIPI1, WIPI2, MAP1LC3B, ATG9B) (Napolitano and Ballabio, 2016).

Although the regulation and role of autophagy in diverse situations has been the focus of much attention, less is known about the autophagic response to physical cues (Dupont and Codogno, 2016; King, 2012). However, recent studies have illuminated the role of autophagy in the translation of mechanical forces into a wide range of biological responses, from the control of cell size and metabolism, to anti-atherogenic effects. The aim of this Review is to present and discuss these recent findings that constitute a novel aspect of the role of the autophagic machinery in physiology and pathophysiology.

Mechanical forces in physiology and pathophysiology

Many cells in multicellular organisms are embedded in a three-dimensional microenvironment where they are constantly challenged with different forms of stress arising from intrinsic biological processes or from the extrinsic physical environment. For example, mesenchymal stem cells preferentially undergo osteogenesis on stiff ECM, whereas they are able to differentiate into neurons on soft ECM (Engler et al., 2006). At the tissue level, mechanical signals contribute to morphogenesis during development and organ functions (Mammoto et al., 2013). For example, forces generated by blood flow directly impact the physiology of the cardiovascular system, which transports pressurized blood, through the process of mechanotransduction (Chien, 2007; Garoffolo and Pesce, 2019). Physical forces from mechanical loading also regulate the balance between bone formation and bone resorption (Alfieri et al., 2019; Curtis et al., 2020; Duncan and Turner, 1995), whereas mechanical forces from inflation play a central role in the regulation of the structure and function of lung tissue (Spieth et al., 2014; Tschumperlin et al., 2010). Furthermore, the relevance of mechanics is obvious in some pathological processes with the most obvious being tissue fibrosis, where the ECM is stiffened. More importantly, altered tissue mechanics are now also recognized as having an active role in driving human diseases, such as cancer (Mohammadi and Sahai, 2018; Papalazarou et al., 2020; Tschumperlin et al., 2018; van Helvert et al., 2018) and microbial pathogenesis (Charles-Orszag et al., 2016; Dufrêne and Persat, 2020).

Mechanosensors and signaling

Mechanotransduction is the process by which cells sense and translate external mechanical forces into internal biochemical signals (Wolfenson et al., 2019). Cells are subjected to a myriad of mechanical cues, such as forces generated by changes in ECM composition, compression, stretching, tension and shear stress; these are either sensed directly by mechanoreceptors or indirectly relayed via the cytoskeleton (Essig et al., 2001; Wang et al., 1993), and transduced to intracellular signaling pathways that regulate fundamental cellular processes, such as cell proliferation, differentiation (Pinheiro and Bellaϊche, 2018) and autophagy (Dupont and Codogno, 2016).

Cells are able to sense extracellular mechanical inputs in multiple ways. For instance, cellular adhesion complexes (both with the ECM and other cells) containing integrins (Kechagia et al., 2019; Sun et al., 2019) or cadherins (Yap et al., 2018) have been identified as mechanosensors. Other mechanosensors include proteoglycans localized in the glycocalyx (Tarbell and Ebong, 2008; Weinbaum et al., 2007), as well as mechanically activated [such as transient receptor potential (TRP) and PIEZO proteins] and mechanosensitive ion channels (Martinac and Poole, 2018; Murthy et al., 2017; O'Neil and Heller, 2005). Although the molecular basis of organelle-based mechanosensitivity remains mostly unclear, several plasma membrane-associated structures, such as the primary cilium (see Box 2) (Praetorius, 2015), microvilli (Du et al., 2004; Guo et al., 2000), caveolae (Sinha et al., 2011) and clathrin-coated pits (Baschieri et al., 2018), have been described as being involved in mechanosensing. Intracellular organelles, including the nucleus (Aureille et al., 2017; Kirby and Lammerding, 2018; Lomakin et al., 2020; Uhler and Shivashankar, 2017; Venturini et al., 2020), endoplasmic reticulum (ER) (Kim et al., 2015), mitochondria (Helle et al., 2017), the Golgi (Guet et al., 2014; Romani et al., 2019), as well as autophagosomes (see Box 1) are also known, or highly suggested, to sense mechanical forces. For example, shear or stretch directly deform organelles such as cilia or nuclei (Praetorius, 2015; Uhler and Shivashankar, 2017), whereas physical forces are capable of indirectly affecting the dynamics of specific organelles (e.g. mitochondria; Helle et al., 2017).

Box 2. The primary cilium

Cilia are microtubule-based organelles that protrude at the cell surface. They are classified as either motile or non-motile according to their microtubule pattern (Satir and Christensen, 2007). Motile cilia generate fluid flow and beat-like movements and are found on the surfaces of epithelial cells lining the airways and reproductive tracts, as well as on epithelial cells of the ependyma and in the brain. In contrast, primary cilia are solitary and non-motile structures present in almost all cell types, with the exception of hepatocytes and some cells of the lymphoid and myeloid lineage (Douanne et al., 2021; Finetti et al., 2014). Structurally, they are composed of an axoneme of nine outer doublet microtubules extending from a basal body that is derived from the mother centriole of the centrosome (ciliogenesis and cell division are mutually exclusive) (Malicki and Johnson, 2017). However, the nine doublet microtubule structure seems oversimplified and has been challenged by recent studies (Kiesel et al., 2020). A transition zone gates the entry of cytoplasmic proteins into the axoneme (Garcia-Gonzalo and Reiter, 2012; Satir and Christensen, 2007). Primary cilia act as a sensory antennae and function during embryonic development, vision, olfaction and mechanotransduction (Goetz and Anderson, 2010; Satir and Christensen, 2007). They respond to different stimuli, such as chemical stimuli (e.g. specific ligand, growth factor, hormone or morphogen recognition; Goetz and Anderson, 2010; Satir and Christensen, 2007) and mechanical stimuli (e.g. a shear stress that may result in bending of the cilium; Ferreira et al., 2019). A variety of signaling pathways are coordinated through this organelle, such as the Hedgehog pathway, the platelet-derived growth factor (PDGF) pathway, the Wnt pathway, G-protein-coupled receptors and ion channels (Anvarian et al., 2019; Nachury and Mick, 2019). Intraflagellar transport (IFT) complexes are essential for the formation of the primary cilium (Nachury and Mick, 2019; Nakayama and Katoh, 2018; Pigino, 2021). The IFT-B complex is composed of 16 proteins and contributes to the transport of proteins to the tip of the primary cilium using the motor protein kinesin 2, whereas the IFT-A complex, which is composed of six proteins, is involved in transport from the tip to the basal body of the primary cilium and utilizes dynein (Nakayama and Katoh, 2018). Defects in the function and/or assembly of primary cilia lead to a group of human diseases collectively known as ciliopathies (Anvarian et al., 2019; Braun and Hildebrandt, 2017).

Once sensed by one of these mechanoreceptors, mechanical forces are able to activate ion influx, as is the case for PIEZO channels (Murthy et al., 2017), or intracellular cytoskeleton-associated signaling molecules, as described for integrins, such as the Rho-family GTPases that connect the cytoskeleton to the plasma membrane lipid bilayer, allowing the transmission of mechanical cues inside the cell (Kechagia et al., 2019; Sun et al., 2019). Downstream intracellular effectors, such as the transcriptional coactivators YAP1 (Yes-associated protein 1) and TAZ (WW domain-containing transcription regulator 1) have also been shown to be involved in the translation of external mechanical forces into internal biochemical signals (Dupont et al., 2011; Panciera et al., 2017; Pocaterra et al., 2020). Readers who are interested in a broader and in-depth discussion of the different types of mechanosensors and intracellular signaling pathways should consult the following relevant reviews (Hoffman et al., 2011; Kechagia et al., 2019; Lim et al., 2018; Panciera et al., 2017; Pinheiro and Bellaϊche, 2018).

Here, we summarize our knowledge of the role of autophagy in the integration of mechanical forces, highlighting the mechanosensors involved and the cellular signaling pathways controlling autophagy, with a discussion of the relevance of this novel aspect of autophagy in physiology and pathophysiology.

Compression and autophagy

In contrast to tension (see below), compression squeezes and shortens cells in the direction of the applied force. The archetypes of tissues that constantly bear compressive forces are the bone, cartilage and teeth. Many physiological (e.g. tissue growth during development) or pathological situations (e.g. inflammation or cancer) are associated with an increase of compression. For example, tumor growth generates compression force that acts on adjacent non-tumorous cells, activating tumorigenic pathways (Fernández-Sánchez et al., 2015).

Compression-induced autophagy has been observed in Dictyostelium (King et al., 2011) and in mammalian cells, including the cervical cancer cell line HeLa (Das et al., 2019; Wang et al., 2019), chondrocytes (Xiang et al., 2019; Xu et al., 2014) and nucleus pulposus cells derived from intervertebral discs (He et al., 2021; Ma et al., 2013). Studies have also confirmed the stimulation of autophagy upon compression in several ex vivo experimental conditions, including bovine and human cartilage explants (Caramés et al., 2012), mouse spinal cords (Tanabe et al., 2011; Zhang et al., 2020), porcine eyes (Porter et al., 2014; Shim et al., 2021) and rat skeletal tibial muscles (Teng et al., 2011) (Fig. 1 and Table 1). Despite this knowledge, the exact role of autophagy induction upon compression remains poorly defined. So far, it has been shown that compression-dependent autophagy inhibits apoptosis in the spinal cord (Lee et al., 2009; Wang et al., 2012; Zhang et al., 2020). The mechanosensors involved and the cellular signaling pathways that control the regulation of compression-dependent autophagy are far from being well understood. The primary cilium has been recently proposed to participate in the stimulation of compression-induced autophagy in vitro in chondrocytes, where ERK and mTOR signaling are suggested to contribute to this stimulation (Xiang et al., 2019) (Fig. 1). However, in breast cancer cell lines subjected to pressure, autophagy induction is independent of the mTOR pathway (King et al., 2011). There is evidence indicating that compression-induced autophagy could also be supported by reactive oxygen species (ROS)-dependent signaling in nucleus pulposus cells (Ma et al., 2013) and lipid-raft-mediated p38 MAPK-dependent processes in HeLa cells (Das et al., 2019). Hypoxia-inducible factor 1α (HIF1α) has also recently been shown to upregulate autophagy in nucleus pulposus-derived stem cells under compression (He et al., 2021).

Fig. 1.

The role of autophagy in the translation of physical forces into biological responses. Diagram illustrating the diverse mechanical forces (shear, stretch or tension, pressure, and forces generated by ECM stiffness) able to induce autophagy. Known mechanosensors and intracellular sensors that activate intracellular signaling pathways to regulate autophagy are depicted. The different cellular responses to mechanotransduction-dependent autophagy are highlighted.

Fig. 1.

The role of autophagy in the translation of physical forces into biological responses. Diagram illustrating the diverse mechanical forces (shear, stretch or tension, pressure, and forces generated by ECM stiffness) able to induce autophagy. Known mechanosensors and intracellular sensors that activate intracellular signaling pathways to regulate autophagy are depicted. The different cellular responses to mechanotransduction-dependent autophagy are highlighted.

Table 1.

Effect of mechanical force on autophagy in various tissues

Effect of mechanical force on autophagy in various tissues
Effect of mechanical force on autophagy in various tissues

The brain is another organ exposed to compression, which occurs in traumatic brain injury (TBI) or subarachnoid hemorrhage (SAH). Interestingly, several laboratories have observed an accumulation of autophagic markers in experimental SAH samples (Lee et al., 2009; Wang et al., 2012) and TBI samples from rodents (Lai et al., 2008; Zhang et al., 2008), as well as in human samples (Clark et al., 2008). Autophagy induction appears to be neuroprotective in SAH by inhibiting apoptosis (Fang et al., 2018; Zhang and Liu, 2020). However, the signaling pathways and mechanosensors involved remain to be uncovered.

Accumulating evidence indicates that compression contributes to the development of other human diseases, including cancer. Indeed, uncontrolled proliferation of cancer cells generates compression that affects migration during metastasis (Cheng et al., 2009; Tse et al., 2012). Tumor growth in vivo has also been shown to exert mechanical compression forces on adjacent non-tumorous cells (Fernández-Sánchez et al., 2015). Since the autophagy pathway is dysregulated during tumorigenesis and compression can upregulate autophagy in cancer cell lines, as mentioned above (Das et al., 2019; King et al., 2011; Wang et al., 2019), it will be of interest to study the role of compression-induced autophagy in tumor biology. Finally, inflammation can be caused by many different factors, including heat, freezing, trauma, chemicals or infectious agents, and is generally associated with an increase in interstitial osmotic pressure (Grimble, 2003; Schwartz et al., 2008, 2009). Considering that autophagy acts mainly through mitophagy-mediated suppression of inflammatory cytokine production (Deretic and Levine, 2018; Levine et al., 2011; Matsuzawa-Ishimoto et al., 2018) in inflammatory diseases, studying the role of mechanical force-induced autophagy should increase our understanding of the pathogenesis of these diseases.

Shear stress and autophagy

Shear stress is a frictional force caused by fluid flow that is parallel to, and acts over, the surface of cells; it is therefore directly linked to fluid viscosity, flow rate and geometry. Thus, by definition, every single cell facing fluid in the human body is constantly dealing with shear stress, in particular endothelial and endocardial cells within cardiovascular tissue, as well as other cells experiencing fluid flow from sources that include urinary, interstitial, lymphatic, nodal, lacunocanalicular and cerebral spinal fluids.

As summarized in Table 1, studies of endothelial cells have concluded that unidirectional or laminar fluid flow promotes autophagy. Importantly, the shear stress applied in these studies (above 10 dyn/cm2, 1 Pa) corresponds to forces observed at atheroprotective sites, such as the descending thoracic aorta (Chiu and Chien, 2011; Gimbrone and García-Cardeña, 2013; Hahn and Schwartz, 2009). However, autophagy appears to be inhibited when oscillatory or low-magnitude fluid flow (below 4 dyn/cm2, 0.4 Pa) is used (Table 1), conditions prevalent at atherosclerosis-prone sites, such as arterial bifurcations and the inner part of curvatures (Chiu and Chien, 2011; Gimbrone and García-Cardeña, 2013; Hahn and Schwartz, 2009). Analyses of ex vivo perfused animal vessels and in vivo animal models have confirmed the effect of fluid flow-induced mechanical force on the autophagic pathway (Ding et al., 2015; Guo et al., 2014; Li et al., 2015; Santovito et al., 2020; Vion et al., 2017; Yang et al., 2016). Importantly, regarding the effect of autophagy induced by high shear stress on atherosclerotic plaque development, it has been demonstrated that hypercholesterolemic mice bearing an endothelial-specific deletion of Atg5 (Apoe−/−; Atg5flox/flox;VE-cadherin-Cre) develop larger atherosclerotic lesions only in normally atheroprotected areas, when compared to littermate controls (Vion et al., 2017). Interestingly, the atheroprotective effect of shear-stress-induced autophagy is mediated by the inhibition of endothelial cell apoptosis and senescence, as well as the inhibition of inflammatory cytokine production (Vion et al., 2017) (Figs 1, 2). However, the exact autophagy-dependent molecular mechanisms driving this protective cell phenotype remain unclear. What we know so far is that under conditions of high shear stress, autophagy downregulates endothelial cell death by facilitating the nuclear shuttling and activation of the anti-apoptotic microRNA miR126-5p (Santovito et al., 2020).

Fig. 2.

Shear stress and autophagy in endothelial and epithelial cells. Illustration of the involvement of autophagy in the translation of shear stress into biological processes in kidney tubular cells (left) and vascular endothelial cells (right). Mechanical forces generated by urinary fluid flow and blood flow are able to induce both non-selective and selective (lipophagy) autophagy pathways in an AMPK-dependent manner. In renal epithelial cells, the stimulation of autophagy and lipophagy, downstream of the primary cilium, are essential for cell size regulation, metabolic reprogramming and the ATP production needed to support energy consuming processes, such as tubular reabsorption, neoglucogenesis and actin cytoskeleton remodeling. This mechanotransduction is accompanied by an induction of mitochondrial biogenesis driven by the PGC1α signaling pathway. In endothelial cells of the descending thoracic aorta, the stimulation of autophagy by an as-yet-unidentified mechanosensor upon high laminar shear stress is important to inhibit endothelial cell apoptosis, senescence and inflammation, and to favor endothelial cell alignment in the direction of blood flow. FAO, fatty acid oxidation; FFA, free fatty acid; OXPHOS, oxidative phosphorylation.

Fig. 2.

Shear stress and autophagy in endothelial and epithelial cells. Illustration of the involvement of autophagy in the translation of shear stress into biological processes in kidney tubular cells (left) and vascular endothelial cells (right). Mechanical forces generated by urinary fluid flow and blood flow are able to induce both non-selective and selective (lipophagy) autophagy pathways in an AMPK-dependent manner. In renal epithelial cells, the stimulation of autophagy and lipophagy, downstream of the primary cilium, are essential for cell size regulation, metabolic reprogramming and the ATP production needed to support energy consuming processes, such as tubular reabsorption, neoglucogenesis and actin cytoskeleton remodeling. This mechanotransduction is accompanied by an induction of mitochondrial biogenesis driven by the PGC1α signaling pathway. In endothelial cells of the descending thoracic aorta, the stimulation of autophagy by an as-yet-unidentified mechanosensor upon high laminar shear stress is important to inhibit endothelial cell apoptosis, senescence and inflammation, and to favor endothelial cell alignment in the direction of blood flow. FAO, fatty acid oxidation; FFA, free fatty acid; OXPHOS, oxidative phosphorylation.

It has been suggested that autophagy inhibits the activity of the transcriptional coactivators YAP1 and TAZ (referred to collectively as YAP/TAZ; Yuan et al., 2020), which are known to regulate inflammation. These data are in line with the fact that YAP/TAZ are active in atheroprone regions that are exposed to disturbed low blood flow and characterized by inefficient autophagy, compared to the atheroprotective regions, which are exposed to undisturbed high laminal blood flow with high levels of autophagy (Nakajima et al., 2017; Wang et al., 2016; Yuan et al., 2020). Shear-stress-dependent autophagy is also important for nitric oxide (NO) production, a crucial molecule that maintains vascular homeostasis in endothelial cells (Bharath et al., 2017, 2014). Indeed, in zones of low shear stress that are prone to develop atherosclerotic plaques, especially in the artery tree, the impairment of autophagic flux induces endothelial NO synthase (eNOS, also known as NOS3) uncoupling, resulting in the production of O2 instead of NO. Restoration of the autophagic flux favors the production of NO by eNOS (Zhang et al., 2018).

Nevertheless, the mechanosensors upstream of autophagy induction in endothelial cells are not well known. Several structures and molecules, including the apical glycocalyx, primary cilia, proteins such as glycoprotein CD31 (also known as PECAM-1) or ion channels, have been suggested to sense fluid shear stress in endothelial cells (Baeyens et al., 2016). However, neither CD31 nor the primary cilium appear to be implicated in autophagy induced by high shear stress (20 dyn/cm2, 2 Pa) in human umbilical vein endothelial cells (HUVECs; Vion et al., 2017). Other key endothelial mechanosensors, including integrins (Tzima et al., 2001; Weinbaum et al., 2007) and specialized plasma membrane-associated organelles (such as caveolae; Yu et al., 2006) have been shown to play a role in the regulation of autophagy, but whether they are involved in fluid-flow-induced autophagy remains to be investigated. Regarding the cellular signaling pathways downstream of mechanosensors, there is evidence indicating that induction of autophagy by fluid flow depends on the redox potential, the NAD-dependent deacetylase SIRT1, the lectin-like oxidized low-density lipoprotein scavenger receptor LOX-1 (also known as OLR1; Ding et al., 2015; Liu et al., 2015; Yuan et al., 2020) and the AMP-activated protein kinase (AMPK)–mTOR pathway (Vion et al., 2017). Other key factors, including phosphoinositide 3-kinase (PI3K) (Wang et al., 2018), focal adhesion kinase (FAK) (Wang et al., 2018; Yan et al., 2019), Rho GTPases (Wang et al., 2018; Yan et al., 2019) and p38 MAPK (Das et al., 2018) have also been suggested to induce autophagy upon shear stress in cancer cell lines, such as the hepatocarcinoma cell line HepG2.

As mentioned above, kidney tubular cells are also subjected to shear stress, which is a crucial factor in renal physiological function (Raghavan and Weisz, 2016; Verschuren et al., 2020). For the past few years, we have been investigating the effect of mechanical forces on kidney epithelial cells and have demonstrated that physiologically relevant shear stress (1 dyn/cm2, 0.1 Pa) induces autophagy in a primary cilia-dependent manner in mouse and human cell lines (Boukhalfa et al., 2020; Miceli et al., 2020; Orhon et al., 2016; Zemirli et al., 2019), as well as in mouse models (Orhon et al., 2016). Autophagy induction in this model is important for the regulation of cell size and stimulation of metabolic reprogramming. Here, mechanotransduction is based on the induction of a selective autophagic pathway, known as lipophagy, that is required for lipid droplet degradation (Singh et al., 2009). Lipophagy induction is accompanied by an upregulation of mitochondrial biogenesis driven by the PGC1α (also known as PPARGC1A) signaling pathway and a stimulation of ATP production, which is needed to support energy-consuming processes such as cell size reduction and renal glucose reabsorption (Miceli et al., 2020) (Fig. 2). This is in line with another study showing that cell metabolism is sensitive to the physical cell microenvironment (Romani et al., 2021).

In response to shear stress, autophagy is stimulated in kidney epithelial cells by the mTOR complex 1 (mTORC1)–AMPK pathway and by Ca2+ influx dependent on the primary cilium Ca2+ channel polycystin 2 (PC2, also known as PKD2) (Orhon et al., 2016). PC2-dependent autophagy is not involved in cell size regulation, in contrast to mTORC1–AMPK-dependent autophagy. The role of PC2-dependent autophagy remains to be determined (for a recent discussion see Peña-Oyarzun et al., 2020). The activation of mTORC1–AMPK depends on the upstream kinase LKB1 (also known as STK11) located in the axoneme (Boehlke et al., 2010; Orhon et al., 2016). More recently, folliculin (FLCN) has been demonstrated to act upstream of LKB1 in controlling AMPK activity, autophagy and cell size regulation (Zemirli et al., 2019).

The most intriguing question that remains to be answered is which ciliary mechanosensitive protein upstream of the FLCN–LKB1–AMPK–mTORC1 axis is involved in inducing autophagy. Along the same lines, studying the role of actin-rich microvilli structures, already known to trigger autophagy upon shear stress in intestinal epithelial cells (Kim et al., 2017), may also help to improve our understanding of mechanotransduction in kidney cells. More generally, it will be of interest to determine to what extent the observations of fluid-flow-induced autophagy in renal tubules help us to better decipher the early steps involved in acute and chronic renal diseases, in which autophagy and urinary fluid flow are known to be deregulated (Choi, 2020; Verschuren et al., 2020). Based on a number of in vivo studies pointing to a reno-protective role of autophagy in autophagy-related (ATG) protein-deficient mice subjected to chronic or acute kidney injury (Choi, 2020), we believe that the deregulation of autophagy induced by mechanical alterations could participate in driving the progression of renal diseases.

Finally, cancer cells can also experience shear stress. Among the first studies to show that shear stress can modulate cell fate by inducing autophagy were in vitro analyses of osteoblast and cancer cell lines subjected to flow by using fluidic pumps (Kim and Yoo, 2013; Lien et al., 2013). For instance, at the primary tumor site, interstitial flow can promote the distribution of tumor-derived cells, whereas circulating tumor cells are also subjected to and exploit the shear stress generated by body fluids (blood, lymph and interstitial fluid) during metastasis (Follain et al., 2020; Swartz and Lund, 2012). Interestingly, shear stress induces autophagy in cancer cell lines (Das et al., 2018; Lien et al., 2013; Wang et al., 2019, 2018; Yan et al., 2019) (see Table 1), which leads by as-yet-unknown means to the stimulation of cell migration and cell invasion at early time points of shear (Wang et al., 2018; Yan et al., 2019) and the induction of cell death at later time points (Lien et al., 2013). Thus, studying how mechanical forces influence autophagy in cancer cells may help to improve our understanding of the progression of tumorigenesis. Overall, even if the exact molecular mechanisms upstream or downstream of autophagic induction upon shear are still not fully understood, accumulating evidence clearly shows that shear stress-induced autophagy plays an important role in controlling a variety of cell responses from the regulation of cell size and metabolism to inflammation and cell death.

Stretching, tension and autophagy

Stretching and tension are related to the force needed to extend a tissue or a cell uniaxially or biaxially. Stretching usually refers to a passive deformation due to the application of external forces, whereas tension is an active force that depends on the elastic properties of cells. Tissues such as muscles are constantly subjected to tension. While the heart muscle is the best characterized example, many other tissues, including bone, tendons, and ligaments, are also exposed to stretching.

Two independent laboratories have provided the first evidence that mechanical forces induce autophagy in vivo by demonstrating that physical exercise is a potent inducer of autophagy in skeletal and cardiac muscles when mice are subjected to training on a treadmill (Grumati et al., 2011; He et al., 2012a). Whether the effect of tension directly modulates autophagy in this setting is still to be investigated. Autophagy induction in muscles during physical activity is important for muscle homeostasis and represents an adaptive response to exercise that ensures effective mitochondrial quality control (Lo Verso et al., 2014). The health benefits of exercise, including life span extension and protection against cardiovascular diseases and diabetes, are clear, but whether these benefits are due in part to autophagy activation is an interesting open question. Physical exercise has been shown to induce autophagy in peripheral tissues (liver, pancreas and adipose tissue) and in the brain (He et al., 2012b). By using stretching devices, stretch-induced autophagy has also been observed in vitro in human patellar tendon fibroblasts isolated from tendon pieces (Chen et al., 2015), trabecular meshwork cells derived from corneal rims (Porter et al., 2014; Shim et al., 2021, 2020) and smooth muscle cells (Ulbricht et al., 2013) (Fig. 1 and Table 1).

Cardiac cells are also subjected to tension. Several pathophysiological conditions, including myocardial infarction, systemic hypertension and pulmonary embolism, lead to an increase in cardiac workload and mechanical forces that are usually associated with pathological cardiac hypertrophy (Nakamura and Sadoshima, 2018). In vitro and in vivo studies have analyzed the effects of mechanical forces on the autophagic pathway in cardiac cells. First, mechanical tension-induced autophagy has been observed in vitro in cultured cardiomyocytes of neonatal rats (Lin et al., 2015, 2014; Yu et al., 2019). Second, autophagy has been shown to be upregulated in the heart during myocardial infarction (Kanamori et al., 2011; Matsui et al., 2007; Yan et al., 2005) and pressure overload induced by transverse aortic constriction (TAC) in a mouse model (Nakai et al., 2007; Zhu et al., 2007). The role of autophagy in this setting appears to be quite complex, because its induction can be protective or detrimental depending on the context, level and duration. Indeed, autophagy protects cardiomyocytes during ischemia (Kanamori et al., 2011; Matsui et al., 2007; Yan et al., 2005), whereas inhibition of autophagy has been shown to improve cardiac function after reperfusion in an ischemia–reperfusion mouse model (Matsui et al., 2007). In parallel, activation of autophagy has been shown to prevent TAC-induced ventricular hypertrophy and improve ventricular function (Ha et al., 2005; McMullen et al., 2004). However, excessive autophagy induction in failing hearts could also lead to cardiomyocyte cell death (Gao et al., 2018; Knaapen et al., 2001; Kostin et al., 2003; Takemura et al., 2006).

Currently, the mechanosensors and cellular signaling pathways that control the regulation of stretch- or tension-induced autophagy are far from being well understood. As discussed above, the primary cilium has been recently shown to regulate stretch-induced autophagy in trabecular meshwork cells (Shim et al., 2021) via AKT-dependent and SMAD2 and SMAD3 (SMAD2/3)-dependent signaling (Fig. 1). However, the role of the primary cilium in sensing stretching and/or tension remains unclear. Studying the role of stretch-sensitive or stretch-activated channels, such as TRP channels including TRPC1 (Bai et al., 2008), that are localized in the cilium could help to better understand this mechanotransduction pathway. In addition to the primary cilium, the muscle-stretch sensor LIM protein (MLP; also known as cysteine and glycine-rich protein 3, CSRP3), which was discovered in the sarcomeric Z-disc and shown to be defective in a subset of cardiomyopathies (Knöll et al., 2002), also regulates autophagy (Rashid et al., 2015). Other mechanosensing proteins that are also able to sense stretching are the stretch-activated ion channels (SACs) (Nilius and Honoré, 2012), including the TRP channel polycystin 1 (PC1, also known as PKD1 or TRPP1), which is required for cardiac hypertrophy (Pedrozo et al., 2015). It will be interesting to study the role of SACs in stretch- or tension-induced autophagy. Furthermore, several molecular chaperones have been found to be essential for tension-induced autophagy in muscle cells, including Hsc70 (heat shock cognate 70, also known as HSPA8) and HspB8 (heat shock protein family B member 8), as well as the co-chaperones BAG3 (BAG co-chaperone 3) and synaptopodin-2 (Arndt et al., 2010; Ulbricht et al., 2013). This particular type of autophagy is referred to as chaperone-assisted autophagy (CASA) (Kettern et al., 2010). In addition, exercise-induced autophagy is controlled by a pro-oxidant complex consisting of regulated in development and DNA damage responses 1 (REDD1, also known as DDIT4) and thioredoxin-interacting protein (TXNIP), which regulates the activity of ATG4B (Qiao et al., 2015). Thus, based on these studies, it would be interesting to determine whether there is a common molecular signature of stretch- or tension-induced autophagy.

Autophagy and the ECM

Although the ECM is not a physical force per se, its meshwork of collagens, glycoproteins and proteoglycans has viscoelastic properties that generate mechanical cues, such as resistance of tension-mediated forces. In tissues, cells do not exist in isolation but are surrounded by other cells and by the ECM produced by the cells themselves. The biochemical composition and biophysical properties of the ECM vary according to the organ type, physiological situation (such as tissue repair) or pathological state (such as fibrosis).

Evidence that ECM stiffness interferes with the autophagic pathway comes from different studies showing that several ECM constituents can modulate autophagy. For example, collagen VI or proteoglycans, including decorin and biglycan, have been identified as autophagic inducers (Castagnaro et al., 2018; Gubbiotti and Iozzo, 2015; Tuloup-Minguez et al., 2011), while the glycoprotein laminin α2 (LAMA2) is known to inhibit the autophagy pathway (Carmignac et al., 2011). ECM-driven autophagy plays a central role in several biological processes, such as angiogenesis, tissue repair and fibrosis (Chen et al., 2020a; Madhu et al., 2020). Conversely, it is worth mentioning that autophagy is able to regulate the turnover of ECM receptors, including integrins and focal adhesion-associated proteins, such as paxillin and vinculin, which are important to support cell migration (Kenific et al., 2016a; Sharifi et al., 2016; Tuloup-Minguez et al., 2011). Based on this, the effect of ECM stiffness itself on autophagy has been investigated, and it has been shown that the autophagic pathway is compromised in non-tumorigenic epithelial cells (MCF10A) cultured in a soft ECM microenvironment (Pavel et al., 2018). Interestingly, this ECM-dependent modulation of autophagy is important to negatively control proliferation and induce cell death. Subsequent studies have confirmed that soft ECM impairs autophagy in both non-malignant and cancer cells (Li et al., 2020; Totaro et al., 2019). However, in contrast to the previously observed role in autophagy initiation (Pavel et al., 2018), the specific effect here is an induction of autophagic flux (Totaro et al., 2019). The reason for this discrepancy remains unknown, but it could be due to differences in the quantitative composition of the ECM used in the in vitro studies. More recently, it has also been reported that changing the substrate stiffness significantly and differentially impacts the autophagy pathway in vascular endothelial and smooth muscle cells (Hu et al., 2021).

Several key factors are known to be involved in the signaling pathways that lead to the induction of ECM-dependent autophagy. First, ECM stiffness interferes with autophagy through modulation of cytoskeleton dynamics and actin-associated regulators, such as the Rho small GTPase and its downstream effector ROCK (Rho-associated protein kinase), which has been previously shown to regulate the endomembrane remodeling process required for the formation of double-membrane autophagic structures (Li et al., 2020). In addition, the transcriptional coactivators YAP/TAZ have been shown to control ECM-dependent autophagy (Pavel et al., 2018; Totaro et al., 2019), and YAP/TAZ directly modulate autophagy by controlling the transcription of actomyosin genes (MLC2, MYH10, MYH14) (Pavel et al., 2018). In addition, YAP/TAZ control the expression of factors that are essential for the autophagic pathway, such as the RAB7 GTPase-activating protein Armus (also known as TBC1D2A; Totaro et al., 2019). However, despite these insights, direct evidence for an involvement of the known mechanosensors that control autophagy in soft or stiff microenvironments is lacking. More generally, other important questions regarding ECM-dependent mechanics and autophagy remain unanswered, such as exactly how autophagy exerts an effect in the differentiation of stem cells that are exposed to different types of ECM. Although ECM-induced autophagy has been suggested to play a role in the acquisition of stemness properties (Li et al., 2020; Totaro et al., 2019), it remains unclear how autophagy impacts cell fate.

The role of autophagy in the integration of mechanical constraints is an emerging field of research, but we are only at the tip of the iceberg, and future studies will be necessary to elucidate this aspect of autophagy in tissue homeostasis and disease. Although it is clear that autophagy is an effector of mechanical forces, it is sometimes difficult to assess whether the accumulation of autophagic markers reflects a true induction of autophagy or a blockade of autophagic degradation. Nevertheless, accumulating in vitro and in vivo evidence indicates that mechanical force-induced autophagy is important in normal physiology, and that its dysregulation is associated with various diseases, despite the fact that this research field is still in its infancy, as the outcomes of mechanical force-dependent autophagy remain challenging to analyze.

Another complication is that, in vivo, most cells are not subjected to a single type of force but to a combination of forces. For example, although fibroblasts in tendons and ligaments are mainly exposed to stretching forces in vivo, endothelial cells lining the vessel surface are subjected to a combination of mechanical forces, including shear, hydrostatic pressure and cycling stretch. Various two-dimensional experimental devices have been used to study changes in the autophagy pathway in response to mechanical forces in vitro (Roccio et al., 2021), but they neither take into account the complexity of mechanical forces, nor reflect what occurs in vivo. Physiologically relevant three-dimensional systems, including organs-on-chips, allow cells to reside in a more in vivo-like environment (Bhatia and Ingber, 2014; Ross et al., 2021). Exploiting this technology might help to better understand the role of mechanical force-induced autophagy in the future, with the aim of promoting tissue repair and regeneration.

We thank Nicolas Kuperwasser for editing and proofreading.

Funding

Our work in this area is supported by institutional funding from Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Université de Paris, Agence Nationale de la Recherche (ANR; R18004KK, R16167KK and R18158KK to P.C.; R18176KK to N.D.) and Fondation pour la Recherche Médicale (FRM; to P.C.).

Alderden
,
J.
,
Rondinelli
,
J.
,
Pepper
,
G.
,
Cummins
,
M.
and
Whitney
,
J.
(
2017
).
Risk factors for pressure injuries among critical care patients: a systematic review
.
Int. J. Nurs. Stud.
71
,
97
-
114
.
Alfieri
,
R.
,
Vassalli
,
M.
and
Viti
,
F.
(
2019
).
Flow-induced mechanotransduction in skeletal cells
.
Biophys. Rev.
11
,
729
-
743
.
Anvarian
,
Z.
,
Mykytyn
,
K.
,
Mukhopadhyay
,
S.
,
Pedersen
,
L. B.
and
Christensen
,
S. T.
(
2019
).
Cellular signalling by primary cilia in development, organ function and disease
.
Nat. Rev. Nephrol.
15
,
199
-
219
.
Argentati
,
C.
,
Morena
,
F.
,
Tortorella
,
I.
,
Bazzucchi
,
M.
,
Porcellati
,
S.
,
Emiliani
,
C.
and
Martino
,
S.
(
2019
).
Insight into mechanobiology: how stem cells feel mechanical forces and orchestrate biological functions
.
Int. J. Mol. Sci.
20
,
5337
.
Arndt
,
V.
,
Dick
,
N.
,
Tawo
,
R.
,
Dreiseidler
,
M.
,
Wenzel
,
D.
,
Hesse
,
M.
,
Fürst
,
D. O.
,
Saftig
,
P.
,
Saint
,
R.
,
Fleischmann
,
B. K.
et al. 
(
2010
).
Chaperone-assisted selective autophagy is essential for muscle maintenance
.
Curr. Biol.
20
,
143
-
148
.
Aureille
,
J.
,
Belaadi
,
N.
and
Guilluy
,
C.
(
2017
).
Mechanotransduction via the nuclear envelope: a distant reflection of the cell surface
.
Curr. Opin. Cell Biol.
44
,
59
-
67
.
Baeyens
,
N.
,
Bandyopadhyay
,
C.
,
Coon
,
B. G.
,
Yun
,
S.
and
Schwartz
,
M. A.
(
2016
).
Endothelial fluid shear stress sensing in vascular health and disease
.
J. Clin. Invest.
126
,
821
-
828
.
Bai
,
C.-X.
,
Giamarchi
,
A.
,
Rodat-Despoix
,
L.
,
Padilla
,
F.
,
Downs
,
T.
,
Tsiokas
,
L.
and
Delmas
,
P.
(
2008
).
Formation of a new receptor-operated channel by heteromeric assembly of TRPP2 and TRPC1 subunits
.
EMBO Rep.
9
,
472
-
479
.
Baschieri
,
F.
,
Dayot
,
S.
,
Elkhatib
,
N.
,
Ly
,
N.
,
Capmany
,
A.
,
Schauer
,
K.
,
Betz
,
T.
,
Vignjevic
,
D. M.
,
Poincloux
,
R.
and
Montagnac
,
G.
(
2018
).
Frustrated endocytosis controls contractility-independent mechanotransduction at clathrin-coated structures
.
Nat. Commun.
9
,
3825
.
Bharath
,
L. P.
,
Mueller
,
R.
,
Li
,
Y.
,
Ruan
,
T.
,
Kunz
,
D.
,
Goodrich
,
R.
,
Mills
,
T.
,
Deeter
,
L.
,
Sargsyan
,
A.
,
Anandh Babu
,
P. V.
et al. 
(
2014
).
Impairment of autophagy in endothelial cells prevents shear-stress-induced increases in nitric oxide bioavailability
.
Can. J. Physiol. Pharmacol.
92
,
605
-
612
.
Bharath
,
L. P.
,
Cho
,
J. M.
,
Park
,
S.-K.
,
Ruan
,
T.
,
Li
,
Y.
,
Mueller
,
R.
,
Bean
,
T.
,
Reese
,
V.
,
Richardson
,
R. S.
,
Cai
,
J.
et al. 
(
2017
).
Endothelial cell autophagy maintains shear stress-induced nitric oxide generation via glycolysis-dependent purinergic signaling to endothelial nitric oxide synthase
.
Arterioscler. Thromb. Vasc. Biol.
37
,
1646
-
1656
.
Bhatia
,
S. N.
and
Ingber
,
D. E.
(
2014
).
Microfluidic organs-on-chips
.
Nat. Biotechnol.
32
,
760
-
772
.
Boehlke
,
C.
,
Kotsis
,
F.
,
Patel
,
V.
,
Braeg
,
S.
,
Voelker
,
H.
,
Bredt
,
S.
,
Beyer
,
T.
,
Janusch
,
H.
,
Hamann
,
C.
,
Gödel
,
M.
et al. 
(
2010
).
Primary cilia regulate mTORC1 activity and cell size through Lkb1
.
Nat. Cell Biol.
12
,
1115
-
1122
.
Boukhalfa
,
A.
,
Nascimbeni
,
A. C.
,
Ramel
,
D.
,
Dupont
,
N.
,
Hirsch
,
E.
,
Gayral
,
S.
,
Laffargue
,
M.
,
Codogno
,
P.
and
Morel
,
E.
(
2020
).
PI3KC2α-dependent and VPS34-independent generation of PI3P controls primary cilium-mediated autophagy in response to shear stress
.
Nat. Commun.
11
,
294
.
Braun
,
D. A.
and
Hildebrandt
,
F.
(
2017
).
Ciliopathies
.
Cold Spring Harb. Perspect. Biol.
9
,
a028191
.
Cambré
,
I.
,
Gaublomme
,
D.
,
Burssens
,
A.
,
Jacques
,
P.
,
Schryvers
,
N.
,
De Muynck
,
A.
,
Meuris
,
L.
,
Lambrecht
,
S.
,
Carter
,
S.
,
de Bleser
,
P.
et al. 
(
2018
).
Mechanical strain determines the site-specific localization of inflammation and tissue damage in arthritis
.
Nat. Commun.
9
,
4613
.
Caramés
,
B.
,
Taniguchi
,
N.
,
Seino
,
D.
,
Blanco
,
F. J.
,
D'Lima
,
D.
and
Lotz
,
M.
(
2012
).
Mechanical injury suppresses autophagy regulators and pharmacologic activation of autophagy results in chondroprotection
.
Arthritis. Rheum.
64
,
1182
-
1192
.
Carmignac
,
V.
,
Svensson
,
M.
,
Körner
,
Z.
,
Elowsson
,
L.
,
Matsumura
,
C.
,
Gawlik
,
K. I.
,
Allamand
,
V.
and
Durbeej
,
M.
(
2011
).
Autophagy is increased in laminin α2 chain-deficient muscle and its inhibition improves muscle morphology in a mouse model of MDC1A
.
Hum. Mol. Genet.
20
,
4891
-
4902
.
Castagnaro
,
S.
,
Chrisam
,
M.
,
Cescon
,
M.
,
Braghetta
,
P.
,
Grumati
,
P.
and
Bonaldo
,
P.
(
2018
).
Extracellular collagen VI Has prosurvival and autophagy instructive properties in mouse fibroblasts
.
Front. Physiol.
9
,
1129
.
Chang
,
C.
,
Jensen
,
L. E.
and
Hurley
,
J. H.
(
2021
).
Autophagosome biogenesis comes out of the black box
.
Nat. Cell Biol.
23
,
450
-
456
.
Charles-Orszag
,
A.
,
Lemichez
,
E.
,
Tran Van Nhieu
,
G.
and
Duménil
,
G.
(
2016
).
Microbial pathogenesis meets biomechanics
.
Curr. Opin. Cell Biol.
38
,
31
-
37
.
Chen
,
H.
,
Chen
,
L.
,
Cheng
,
B.
and
Jiang
,
C.
(
2015
).
Cyclic mechanical stretching induces autophagic cell death in tenofibroblasts through activation of prostaglandin E2 production
.
Cell. Physiol. Biochem.
36
,
24
-
33
.
Chen
,
C. G.
,
Gubbiotti
,
M. A.
,
Kapoor
,
A.
,
Han
,
X.
,
Yu
,
Y.
,
Linhardt
,
R. J.
and
Iozzo
,
R. V.
(
2020a
).
Autophagic degradation of HAS2 in endothelial cells: A novel mechanism to regulate angiogenesis
.
Matrix Biol.
90
,
1
-
19
.
Chen
,
S.
,
Qin
,
L.
,
Wu
,
X.
,
Fu
,
X.
,
Lin
,
S.
,
Chen
,
D.
,
Xiao
,
G.
,
Shao
,
Z.
and
Cao
,
H.
(
2020b
).
Moderate fluid shear stress regulates heme oxygenase-1 expression to promote autophagy and ECM homeostasis in the nucleus pulposus cells
.
Front. Cell Dev. Biol.
8
,
127
.
Cheng
,
G.
,
Tse
,
J.
,
Jain
,
R. K.
and
Munn
,
L. L.
(
2009
).
Micro-environmental mechanical stress controls tumor spheroid size and morphology by suppressing proliferation and inducing apoptosis in cancer cells
.
PLoS ONE
4
,
e4632
.
Chien
,
S.
(
2007
).
Mechanotransduction and endothelial cell homeostasis: the wisdom of the cell
.
Am. J. Physiol. Heart Circ. Physiol.
292
,
H1209
-
H1224
.
Chiu
,
J.-J.
and
Chien
,
S.
(
2011
).
Effects of disturbed flow on vascular endothelium: pathophysiological basis and clinical perspectives
.
Physiol. Rev.
91
,
327
-
387
.
Choi
,
M. E.
(
2020
).
Autophagy in kidney disease
.
Annu. Rev. Physiol.
82
,
297
-
322
.
Clark
,
R. S. B.
,
Bayir
,
H.
,
Chu
,
C. T.
,
Alber
,
S. M.
,
Kochanek
,
P. M.
and
Watkins
,
S. C.
(
2008
).
Autophagy is increased in mice after traumatic brain injury and is detectable in human brain after trauma and critical illness
.
Autophagy
4
,
88
-
90
.
Conway
,
D. E.
and
Schwartz
,
M. A.
(
2013
).
Flow-dependent cellular mechanotransduction in atherosclerosis
.
J. Cell Sci.
126
,
5101
-
5109
.
Curtis
,
K. J.
,
Oberman
,
A. G.
and
Niebur
,
G. L.
(
2020
).
Effects of mechanobiological signaling in bone marrow on skeletal health
.
Ann. N. Y. Acad. Sci.
1460
,
11
-
24
.
Das
,
J.
,
Maji
,
S.
,
Agarwal
,
T.
,
Chakraborty
,
S.
and
Maiti
,
T. K.
(
2018
).
Hemodynamic shear stress induces protective autophagy in HeLa cells through lipid raft-mediated mechanotransduction
.
Clin. Exp. Metastasis
35
,
135
-
148
.
Das
,
J.
,
Agarwal
,
T.
,
Chakraborty
,
S.
and
Maiti
,
T. K.
(
2019
).
Compressive stress-induced autophagy promotes invasion of HeLa cells by facilitating protein turnover in vitro
.
Exp. Cell Res.
381
,
201
-
207
.
Deretic
,
V.
and
Levine
,
B.
(
2018
).
Autophagy balances inflammation in innate immunity
.
Autophagy
14
,
243
-
251
.
Ding
,
Z.
,
Liu
,
S.
,
Deng
,
X.
,
Fan
,
Y.
,
Wang
,
X.
and
Mehta
,
J. L.
(
2015
).
Hemodynamic shear stress modulates endothelial cell autophagy: role of LOX-1
.
Int. J. Cardiol.
184
,
86
-
95
.
Dong
,
G.
,
Yang
,
S.
,
Cao
,
X.
,
Yu
,
N.
,
Yu
,
J.
and
Qu
,
X.
(
2017
).
Low shear stress-induced autophagy alleviates cell apoptosis in HUVECs
.
Mol. Med. Rep.
15
,
3076
-
3082
.
Douanne
,
T.
,
Stinchcombe
,
J. C.
and
Griffiths
,
G. M.
(
2021
).
Teasing out function from morphology: similarities between primary cilia and immune synapses
.
J. Cell Biol.
220
,
e202102089
.
Du
,
Z.
,
Duan
,
Y.
,
Yan
,
Q.
,
Weinstein
,
A. M.
,
Weinbaum
,
S.
and
Wang
,
T.
(
2004
).
Mechanosensory function of microvilli of the kidney proximal tubule
.
Proc. Natl. Acad. Sci. USA
101
,
13068
-
13073
.
Dufrêne
,
Y. F.
and
Persat
,
A.
(
2020
).
Mechanomicrobiology: how bacteria sense and respond to forces
.
Nat. Rev. Microbiol.
18
,
227
-
240
.
Duncan
,
R. L.
and
Turner
,
C. H.
(
1995
).
Mechanotransduction and the functional response of bone to mechanical strain
.
Calcif. Tissue Int.
57
,
344
-
358
.
Dupont
,
N.
and
Codogno
,
P.
(
2016
).
Autophagy transduces physical constraints into biological responses
.
Int. J. Biochem. Cell Biol.
79
,
419
-
426
.
Dupont
,
S.
,
Morsut
,
L.
,
Aragona
,
M.
,
Enzo
,
E.
,
Giulitti
,
S.
,
Cordenonsi
,
M.
,
Zanconato
,
F.
,
Le Digabel
,
J.
,
Forcato
,
M.
,
Bicciato
,
S.
et al. 
(
2011
).
Role of YAP/TAZ in mechanotransduction
.
Nature
474
,
179
-
183
.
Engler
,
A. J.
,
Sen
,
S.
,
Sweeney
,
H. L.
and
Discher
,
D. E.
(
2006
).
Matrix elasticity directs stem cell lineage specification
.
Cell
126
,
677
-
689
.
Essig
,
M.
,
Terzi
,
F.
,
Burtin
,
M.
and
Friedlander
,
G.
(
2001
).
Mechanical strains induced by tubular flow affect the phenotype of proximal tubular cells
.
Am. J. Physiol. Renal Physiol.
281
,
F751
-
F762
.
Fang
,
Y.
,
Chen
,
S.
,
Reis
,
C.
and
Zhang
,
J.
(
2018
).
The role of autophagy in subarachnoid hemorrhage: an update
.
Curr. Neuropharmacol.
16
,
1255
-
1266
.
Feng
,
Q.
and
Kornmann
,
B.
(
2018
).
Mechanical forces on cellular organelles
.
J. Cell Sci.
131
,
jcs218479
.
Fernández-Sánchez
,
M. E.
,
Barbier
,
S.
,
Whitehead
,
J.
,
Béalle
,
G.
,
Michel
,
A.
,
Latorre-Ossa
,
H.
,
Rey
,
C.
,
Fouassier
,
L.
,
Claperon
,
A.
,
Brullé
,
L.
et al. 
(
2015
).
Mechanical induction of the tumorigenic β-catenin pathway by tumour growth pressure
.
Nature
523
,
92
-
95
.
Ferreira
,
R. R.
,
Fukui
,
H.
,
Chow
,
R.
,
Vilfan
,
A.
and
Vermot
,
J.
(
2019
).
The cilium as a force sensor-myth versus reality
.
J. Cell Sci.
132
,
jcs213496
.
Finetti
,
F.
,
Patrussi
,
L.
,
Masi
,
G.
,
Onnis
,
A.
,
Galgano
,
D.
,
Lucherini
,
O. M.
,
Pazour
,
G. J.
and
Baldari
,
C. T.
(
2014
).
Specific recycling receptors are targeted to the immune synapse by the intraflagellar transport system
.
J. Cell Sci.
127
,
1924
-
1937
.
Follain
,
G.
,
Herrmann
,
D.
,
Harlepp
,
S.
,
Hyenne
,
V.
,
Osmani
,
N.
,
Warren
,
S. C.
,
Timpson
,
P.
and
Goetz
,
J. G.
(
2020
).
Fluids and their mechanics in tumour transit: shaping metastasis
.
Nat. Rev. Cancer
20
,
107
-
124
.
Füllgrabe
,
J.
,
Klionsky
,
D. J.
and
Joseph
,
B.
(
2014
).
The return of the nucleus: transcriptional and epigenetic control of autophagy
.
Nat. Rev. Mol. Cell Biol.
15
,
65
-
74
.
Gao
,
W.
,
Zhou
,
Z.
,
Liang
,
B.
,
Huang
,
Y.
,
Yang
,
Z.
,
Chen
,
Y.
,
Zhang
,
L.
,
Yan
,
C.
,
Wang
,
J.
,
Lu
,
L.
et al. 
(
2018
).
Inhibiting receptor of advanced glycation end products attenuates pressure overload-induced cardiac dysfunction by preventing excessive autophagy
.
Front. Physiol.
9
,
1333
.
Garcia-Arcos
,
J. M.
,
Chabrier
,
R.
,
Deygas
,
M.
,
Nader
,
G.
,
Barbier
,
L.
,
Sáez
,
P. J.
,
Mathur
,
A.
,
Vargas
,
P.
and
Piel
,
M.
(
2019
).
Reconstitution of cell migration at a glance
.
J. Cell Sci.
132
,
jcs225565
.
Garcia-Gonzalo
,
F. R.
and
Reiter
,
J. F.
(
2012
).
Scoring a backstage pass: mechanisms of ciliogenesis and ciliary access
.
J. Cell Biol.
197
,
697
-
709
.
Garoffolo
,
G.
and
Pesce
,
M.
(
2019
).
Mechanotransduction in the cardiovascular system: from developmental origins to homeostasis and pathology
.
Cells
8
,
1607
.
Gimbrone
,
M. A.
, Jr.
and
García-Cardeña
,
G.
(
2013
).
Vascular endothelium, hemodynamics, and the pathobiology of atherosclerosis
.
Cardiovasc. Pathol.
22
,
9
-
15
.
Goetz
,
S. C.
and
Anderson
,
K. V.
(
2010
).
The primary cilium: a signalling centre during vertebrate development
.
Nat. Rev. Genet.
11
,
331
-
344
.
Grimble
,
R. F.
(
2003
).
Inflammatory response in the elderly
.
Curr. Opin. Clin. Nutr. Metab. Care
6
,
21
-
29
.
Grumati
,
P.
,
Coletto
,
L.
,
Schiavinato
,
A.
,
Castagnaro
,
S.
,
Bertaggia
,
E.
,
Sandri
,
M.
and
Bonaldo
,
P.
(
2011
).
Physical exercise stimulates autophagy in normal skeletal muscles but is detrimental for collagen VI-deficient muscles
.
Autophagy
7
,
1415
-
1423
.
Gubas
,
A.
and
Dikic
,
I.
(
2021
).
A guide to the regulation of selective autophagy receptors
.
FEBS J.
[Epub]
Gubbiotti
,
M. A.
and
Iozzo
,
R. V.
(
2015
).
Proteoglycans regulate autophagy via outside-in signaling: an emerging new concept
.
Matrix Biol.
48
,
6
-
13
.
Guet
,
D.
,
Mandal
,
K.
,
Pinot
,
M.
,
Hoffmann
,
J.
,
Abidine
,
Y.
,
Sigaut
,
W.
,
Bardin
,
S.
,
Schauer
,
K.
,
Goud
,
B.
and
Manneville
,
J.-B.
(
2014
).
Mechanical role of actin dynamics in the rheology of the Golgi complex and in Golgi-associated trafficking events
.
Curr. Biol.
24
,
1700
-
1711
.
Guo
,
P.
,
Weinstein
,
A. M.
and
Weinbaum
,
S.
(
2000
).
A hydrodynamic mechanosensory hypothesis for brush border microvilli
.
Am. J. Physiol. Renal Physiol.
279
,
F698
-
F712
.
Guo
,
F.
,
Li
,
X.
,
Peng
,
J.
,
Tang
,
Y.
,
Yang
,
Q.
,
Liu
,
L.
,
Wang
,
Z.
,
Jiang
,
Z.
,
Xiao
,
M.
,
Ni
,
C.
et al. 
(
2014
).
Autophagy regulates vascular endothelial cell eNOS and ET-1 expression induced by laminar shear stress in an ex vivo perfused system
.
Ann. Biomed. Eng.
42
,
1978
-
1988
.
Ha
,
T.
,
Li
,
Y.
,
Gao
,
X.
,
McMullen
,
J. R.
,
Shioi
,
T.
,
Izumo
,
S.
,
Kelley
,
J. L.
,
Zhao
,
A.
,
Haddad
,
G. E.
,
Williams
,
D. L.
et al. 
(
2005
).
Attenuation of cardiac hypertrophy by inhibiting both mTOR and NFκB activation in vivo
.
Free Radic. Biol. Med.
39
,
1570
-
1580
.
Hahn
,
C.
and
Schwartz
,
M. A.
(
2009
).
Mechanotransduction in vascular physiology and atherogenesis
.
Nat. Rev. Mol. Cell Biol.
10
,
53
-
62
.
He
,
C.
,
Bassik
,
M. C.
,
Moresi
,
V.
,
Sun
,
K.
,
Wei
,
Y.
,
Zou
,
Z.
,
An
,
Z.
,
Loh
,
J.
,
Fisher
,
J.
,
Sun
,
Q.
et al. 
(
2012a
).
Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis
.
Nature
481
,
511
-
515
.
He
,
C.
,
Sumpter
,
R.
, Jr.
and
Levine
,
B.
(
2012b
).
Exercise induces autophagy in peripheral tissues and in the brain
.
Autophagy
8
,
1548
-
1551
.
He
,
R.
,
Wang
,
Z.
,
Cui
,
M.
,
Liu
,
S.
,
Wu
,
W.
,
Chen
,
M.
,
Wu
,
Y.
,
Qu
,
Y.
,
Lin
,
H.
,
Chen
,
S.
et al. 
(
2021
).
HIF1A alleviates compression-induced apoptosis of nucleus pulposus derived stem cells via upregulating autophagy
.
Autophagy
[Epub]
Helle
,
S. C. J.
,
Feng
,
Q.
,
Aebersold
,
M. J.
,
Hirt
,
L.
,
Grüter
,
R. R.
,
Vahid
,
A.
,
Sirianni
,
A.
,
Mostowy
,
S.
,
Snedeker
,
J. G.
,
Šarić
,
A.
et al. 
(
2017
).
Mechanical force induces mitochondrial fission
.
eLife
6
,
e30292
.
Hernández-Cáceres
,
M. P.
,
Munoz
,
L.
,
Pradenas
,
J. M.
,
Pena
,
F.
,
Lagos
,
P.
,
Aceiton
,
P.
,
Owen
,
G. I.
,
Morselli
,
E.
,
Criollo
,
A.
,
Ravasio
,
A.
et al. 
(
2021
).
Mechanobiology of autophagy: the unexplored side of cancer
.
Front. Oncol.
11
,
632956
.
Hoffman
,
B. D.
,
Grashoff
,
C.
and
Schwartz
,
M. A.
(
2011
).
Dynamic molecular processes mediate cellular mechanotransduction
.
Nature
475
,
316
-
323
.
Hu
,
M.
,
Jia
,
F.
,
Huang
,
W.-P.
,
Li
,
X.
,
Hu
,
D.-F.
,
Wang
,
J.
,
Ren
,
K.-F.
,
Fu
,
G.-S.
,
Wang
,
Y.-B.
and
Ji
,
J.
(
2021
).
Substrate stiffness differentially impacts autophagy of endothelial cells and smooth muscle cells
.
Bioact. Mater.
6
,
1413
-
1422
.
Janmey
,
P. A.
and
Miller
,
R. T.
(
2011
).
Mechanisms of mechanical signaling in development and disease
.
J. Cell Sci.
124
,
9
-
18
.
Janota
,
C. S.
,
Calero-Cuenca
,
F. J.
and
Gomes
,
E. R.
(
2020
).
The role of the cell nucleus in mechanotransduction
.
Curr. Opin. Cell Biol.
63
,
204
-
211
.
Johansen
,
T.
and
Lamark
,
T.
(
2020
).
Selective autophagy: ATG8 family proteins, LIR motifs and cargo receptors
.
J. Mol. Biol.
432
,
80
-
103
.
Kanamori
,
H.
,
Takemura
,
G.
,
Goto
,
K.
,
Maruyama
,
R.
,
Tsujimoto
,
A.
,
Ogino
,
A.
,
Takeyama
,
T.
,
Kawaguchi
,
T.
,
Watanabe
,
T.
,
Fujiwara
,
T.
et al. 
(
2011
).
The role of autophagy emerging in postinfarction cardiac remodelling
.
Cardiovasc. Res.
91
,
330
-
339
.
Kawabata
,
T.
and
Yoshimori
,
T.
(
2020
).
Autophagosome biogenesis and human health
.
Cell Discov.
6
,
33
.
Kechagia
,
J. Z.
,
Ivaska
,
J.
and
Roca-Cusachs
,
P.
(
2019
).
Integrins as biomechanical sensors of the microenvironment
.
Nat. Rev. Mol. Cell Biol.
20
,
457
-
473
.
Kenific
,
C. M.
,
Stehbens
,
S. J.
,
Goldsmith
,
J.
,
Leidal
,
A. M.
,
Faure
,
N.
,
Ye
,
J.
,
Wittmann
,
T.
and
Debnath
,
J.
(
2016a
).
NBR1 enables autophagy-dependent focal adhesion turnover
.
J. Cell Biol.
212
,
577
-
590
.
Kenific
,
C. M.
,
Wittmann
,
T.
and
Debnath
,
J.
(
2016b
).
Autophagy in adhesion and migration
.
J. Cell Sci.
129
,
3685
-
3693
.
Kettern
,
N.
,
Dreiseidler
,
M.
,
Tawo
,
R.
and
Höhfeld
,
J.
(
2010
).
Chaperone-assisted degradation: multiple paths to destruction
.
Biol. Chem.
391
,
481
-
489
.
Khaminets
,
A.
,
Behl
,
C.
and
Dikic
,
I.
(
2016
).
Ubiquitin-dependent and independent signals in selective autophagy
.
Trends Cell Biol.
26
,
6
-
16
.
Kiesel
,
P.
,
Alvarez Viar
,
G.
,
Tsoy
,
N.
,
Maraspini
,
R.
,
Gorilak
,
P.
,
Varga
,
V.
,
Honigmann
,
A.
and
Pigino
,
G.
(
2020
).
The molecular structure of mammalian primary cilia revealed by cryo-electron tomography
.
Nat. Struct. Mol. Biol.
27
,
1115
-
1124
.
Kim
,
C. H.
and
Yoo
,
Y.-M.
(
2013
).
Fluid shear stress and melatonin in combination activate anabolic proteins in MC3T3-E1 osteoblast cells
.
J. Pineal Res.
54
,
453
-
461
.
Kim
,
T.-J.
,
Joo
,
C.
,
Seong
,
J.
,
Vafabakhsh
,
R.
,
Botvinick
,
E. L.
,
Berns
,
M. W.
,
Palmer
,
A. E.
,
Wang
,
N.
,
Ha
,
T.
,
Jakobsson
,
E.
et al. 
(
2015
).
Distinct mechanisms regulating mechanical force-induced Ca2+ signals at the plasma membrane and the ER in human MSCs
.
eLife
4
,
e04876
.
Kim
,
S. W.
,
Ehrman
,
J.
,
Ahn
,
M.-R.
,
Kondo
,
J.
,
Lopez
,
A. A. M.
,
Oh
,
Y. S.
,
Kim
,
X. H.
,
Crawley
,
S. W.
,
Goldenring
,
J. R.
,
Tyska
,
M. J.
et al. 
(
2017
).
Shear stress induces noncanonical autophagy in intestinal epithelial monolayers
.
Mol. Biol. Cell
28
,
3043
-
3056
.
King
,
J. S.
(
2012
).
Mechanical stress meets autophagy: potential implications for physiology and pathology
.
Trends Mol. Med.
18
,
583
-
588
.
King
,
J. S.
,
Veltman
,
D. M.
and
Insall
,
R. H.
(
2011
).
The induction of autophagy by mechanical stress
.
Autophagy
7
,
1490
-
1499
.
Kirby
,
T. J.
and
Lammerding
,
J.
(
2018
).
Emerging views of the nucleus as a cellular mechanosensor
.
Nat. Cell Biol.
20
,
373
-
381
.
Knaapen
,
M. W. M.
,
Davies
,
M. J.
,
De Bie
,
M.
,
Haven
,
A. J.
,
Martinet
,
W.
and
Kockx
,
M. M.
(
2001
).
Apoptotic versus autophagic cell death in heart failure
.
Cardiovasc. Res.
51
,
304
-
312
.
Knöll
,
R.
,
Hoshijima
,
M.
,
Hoffman
,
H. M.
,
Person
,
V.
,
Lorenzen-Schmidt
,
I.
,
Bang
,
M.-L.
,
Hayashi
,
T.
,
Shiga
,
N.
,
Yasukawa
,
H.
,
Schaper
,
W.
et al. 
(
2002
).
The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy
.
Cell
111
,
943
-
955
.
Kostin
,
S.
,
Pool
,
L.
,
Elsässer
,
A.
,
Hein
,
S.
,
Drexler
,
H. C. A.
,
Arnon
,
E.
,
Hayakawa
,
Y.
,
Zimmermann
,
R.
,
Bauer
,
E.
,
Klövekorn
,
W.-P.
et al. 
(
2003
).
Myocytes die by multiple mechanisms in failing human hearts
.
Circ. Res.
92
,
715
-
724
.
Lai
,
Y.
,
Hickey
,
R. W.
,
Chen
,
Y.
,
Bayir
,
H.
,
Sullivan
,
M. L.
,
Chu
,
C. T.
,
Kochanek
,
P. M.
,
Dixon
,
C. E.
,
Jenkins
,
L. W.
,
Graham
,
S. H.
et al. 
(
2008
).
Autophagy is increased after traumatic brain injury in mice and is partially inhibited by the antioxidant γ-glutamylcysteinyl ethyl ester
.
J. Cereb. Blood Flow Metab.
28
,
540
-
550
.
Lee
,
J.-Y.
,
He
,
Y.
,
Sagher
,
O.
,
Keep
,
R.
,
Hua
,
Y.
and
Xi
,
G.
(
2009
).
Activated autophagy pathway in experimental subarachnoid hemorrhage
.
Brain Res.
1287
,
126
-
135
.
Levine
,
B.
and
Kroemer
,
G.
(
2019
).
Biological functions of autophagy genes: a disease perspective
.
Cell
176
,
11
-
42
.
Levine
,
B.
,
Mizushima
,
N.
and
Virgin
,
H. W.
(
2011
).
Autophagy in immunity and inflammation
.
Nature
469
,
323
-
335
.
Li
,
R.
,
Jen
,
N.
,
Wu
,
L.
,
Lee
,
J.
,
Fang
,
K.
,
Quigley
,
K.
,
Lee
,
K.
,
Wang
,
S.
,
Zhou
,
B.
,
Vergnes
,
L.
et al. 
(
2015
).
Disturbed flow induces autophagy, but impairs autophagic flux to perturb mitochondrial homeostasis
.
Antioxid. Redox Signal.
23
,
1207
-
1219
.
Li
,
Y.
,
Randriantsilefisoa
,
R.
,
Chen
,
J.
,
Cuellar-Camacho
,
J. L.
,
Liang
,
W.
and
Li
,
W.
(
2020
).
Matrix stiffness regulates chemosensitivity, stemness characteristics, and autophagy in breast cancer cells
.
ACS Appl. Bio Mater.
3
,
4474
-
4485
.
Lien
,
S.-C.
,
Chang
,
S.-F.
,
Lee
,
P.-L.
,
Wei
,
S.-Y.
,
Chang
,
M. D.-T.
,
Chang
,
J.-Y.
and
Chiu
,
J.-J.
(
2013
).
Mechanical regulation of cancer cell apoptosis and autophagy: roles of bone morphogenetic protein receptor, Smad1/5, and p38 MAPK
.
Biochim. Biophys. Acta (BBA) Mol. Cell Res.
1833
,
3124
-
3133
.
Lim
,
C.-G.
,
Jang
,
J.
and
Kim
,
C.
(
2018
).
Cellular machinery for sensing mechanical force
.
BMB Rep.
51
,
623
-
629
.
Lin
,
L.
,
Tang
,
C.
,
Xu
,
J.
,
Ye
,
Y.
,
Weng
,
L.
,
Wei
,
W.
,
Ge
,
J.
,
Liu
,
X.
and
Zou
,
Y.
(
2014
).
Mechanical stress triggers cardiomyocyte autophagy through angiotensin II type 1 receptor-mediated p38MAP kinase independently of angiotensin II
.
PLoS ONE
9
,
e89629
.
Lin
,
L.
,
Liu
,
X.
,
Xu
,
J.
,
Weng
,
L.
,
Ren
,
J.
,
Ge
,
J.
and
Zou
,
Y.
(
2015
).
High-density lipoprotein inhibits mechanical stress-induced cardiomyocyte autophagy and cardiac hypertrophy through angiotensin II type 1 receptor-mediated PI3K/Akt pathway
.
J. Cell. Mol. Med.
19
,
1929
-
1938
.
Liu
,
J.
,
Bi
,
X.
,
Chen
,
T.
,
Zhang
,
Q.
,
Wang
,
S.-X.
,
Chiu
,
J.-J.
,
Liu
,
G.-S.
,
Zhang
,
Y.
,
Bu
,
P.
and
Jiang
,
F.
(
2015
).
Shear stress regulates endothelial cell autophagy via redox regulation and Sirt1 expression
.
Cell Death Dis.
6
,
e1827
.
Lo Verso
,
F.
,
Carnio
,
S.
,
Vainshtein
,
A.
and
Sandri
,
M.
(
2014
).
Autophagy is not required to sustain exercise and PRKAA1/AMPK activity but is important to prevent mitochondrial damage during physical activity
.
Autophagy
10
,
1883
-
1894
.
Lomakin
,
A. J.
,
Cattin
,
C. J.
,
Cuvelier
,
D.
,
Alraies
,
Z.
,
Molina
,
M.
,
Nader
,
G. P. F.
,
Srivastava
,
N.
,
Sáez
,
P. J.
,
Garcia-Arcos
,
J. M.
,
Zhitnyak
,
I. Y.
et al. 
(
2020
).
The nucleus acts as a ruler tailoring cell responses to spatial constraints
.
Science
370
,
eaba2894
.
Ma
,
K.-G.
,
Shao
,
Z.-W.
,
Yang
,
S.-H.
,
Wang
,
J.
,
Wang
,
B.-C.
,
Xiong
,
L.-M.
,
Wu
,
Q.
and
Chen
,
S.-F.
(
2013
).
Autophagy is activated in compression-induced cell degeneration and is mediated by reactive oxygen species in nucleus pulposus cells exposed to compression
.
Osteoarthritis Cartilage
21
,
2030
-
2038
.
Madhu
,
V.
,
Guntur
,
A. R.
and
Risbud
,
M. V.
(
2020
).
Role of autophagy in intervertebral disc and cartilage function: implications in health and disease
.
Matrix Biol.
100
,
207
-
220
.
Maeda
,
S.
,
Yamamoto
,
H.
,
Kinch
,
L. N.
,
Garza
,
C. M.
,
Takahashi
,
S.
,
Otomo
,
C.
,
Grishin
,
N. V.
,
Forli
,
S.
,
Mizushima
,
N.
and
Otomo
,
T.
(
2020
).
Structure, lipid scrambling activity and role in autophagosome formation of ATG9A
.
Nat. Struct. Mol. Biol.
27
,
1194
-
1201
.
Malicki
,
J. J.
and
Johnson
,
C. A.
(
2017
).
The cilium: cellular antenna and central processing unit
.
Trends Cell Biol.
27
,
126
-
140
.
Mammoto
,
A.
,
Mammoto
,
T.
and
Ingber
,
D. E.
(
2012
).
Mechanosensitive mechanisms in transcriptional regulation
.
J. Cell Sci.
125
,
3061
-
3073
.
Mammoto
,
T.
,
Mammoto
,
A.
and
Ingber
,
D. E.
(
2013
).
Mechanobiology and developmental control
.
Annu. Rev. Cell Dev. Biol.
29
,
27
-
61
.
Martinac
,
B.
and
Poole
,
K.
(
2018
).
Mechanically activated ion channels
.
Int. J. Biochem. Cell Biol.
97
,
104
-
107
.
Matsui
,
Y.
,
Takagi
,
H.
,
Qu
,
X.
,
Abdellatif
,
M.
,
Sakoda
,
H.
,
Asano
,
T.
,
Levine
,
B.
and
Sadoshima
,
J.
(
2007
).
Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy
.
Circ. Res.
100
,
914
-
922
.
Matsuzawa-Ishimoto
,
Y.
,
Hwang
,
S.
and
Cadwell
,
K.
(
2018
).
Autophagy and inflammation
.
Annu. Rev. Immunol.
36
,
73
-
101
.
McMullen
,
J. R.
,
Sherwood
,
M. C.
,
Tarnavski
,
O.
,
Zhang
,
L.
,
Dorfman
,
A. L.
,
Shioi
,
T.
and
Izumo
,
S.
(
2004
).
Inhibition of mTOR signaling with rapamycin regresses established cardiac hypertrophy induced by pressure overload
.
Circulation
109
,
3050
-
3055
.
Miceli
,
C.
,
Roccio
,
F.
,
Penalva-Mousset
,
L.
,
Burtin
,
M.
,
Leroy
,
C.
,
Nemazanyy
,
I.
,
Kuperwasser
,
N.
,
Pontoglio
,
M.
,
Friedlander
,
G.
,
Morel
,
E.
et al. 
(
2020
).
The primary cilium and lipophagy translate mechanical forces to direct metabolic adaptation of kidney epithelial cells
.
Nat. Cell Biol.
22
,
1091
-
1102
.
Mizushima
,
N.
and
Komatsu
,
M.
(
2011
).
Autophagy: renovation of cells and tissues
.
Cell
147
,
728
-
741
.
Mizushima
,
N.
,
Yoshimori
,
T.
and
Ohsumi
,
Y.
(
2011
).
The role of Atg proteins in autophagosome formation
.
Annu. Rev. Cell Dev. Biol.
27
,
107
-
132
.
Mohammadi
,
H.
and
Sahai
,
E.
(
2018
).
Mechanisms and impact of altered tumour mechanics
.
Nat. Cell Biol.
20
,
766
-
774
.
Moreau
,
H. D.
,
Piel
,
M.
,
Voituriez
,
R.
and
Lennon-Duménil
,
A.-M.
(
2018
).
Integrating physical and molecular insights on immune cell migration
.
Trends Immunol.
39
,
632
-
643
.
Murthy
,
S. E.
,
Dubin
,
A. E.
and
Patapoutian
,
A.
(
2017
).
Piezos thrive under pressure: mechanically activated ion channels in health and disease
.
Nat. Rev. Mol. Cell Biol.
18
,
771
-
783
.
Nachury
,
M. V.
and
Mick
,
D. U.
(
2019
).
Establishing and regulating the composition of cilia for signal transduction
.
Nat. Rev. Mol. Cell Biol.
20
,
389
-
405
.
Nakai
,
A.
,
Yamaguchi
,
O.
,
Takeda
,
T.
,
Higuchi
,
Y.
,
Hikoso
,
S.
,
Taniike
,
M.
,
Omiya
,
S.
,
Mizote
,
I.
,
Matsumura
,
Y.
,
Asahi
,
M.
et al. 
(
2007
).
The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress
.
Nat. Med.
13
,
619
-
624
.
Nakajima
,
H.
,
Yamamoto
,
K.
,
Agarwala
,
S.
,
Terai
,
K.
,
Fukui
,
H.
,
Fukuhara
,
S.
,
Ando
,
K.
,
Miyazaki
,
T.
,
Yokota
,
Y.
,
Schmelzer
,
E.
et al. 
(
2017
).
Flow-dependent endothelial YAP regulation contributes to vessel maintenance
.
Dev. Cell
40
,
523
-
536.e6
.
Nakamura
,
M.
and
Sadoshima
,
J.
(
2018
).
Mechanisms of physiological and pathological cardiac hypertrophy
.
Nat. Rev. Cardiol.
15
,
387
-
407
.
Nakatogawa
,
H.
,
Suzuki
,
K.
,
Kamada
,
Y.
and
Ohsumi
,
Y.
(
2009
).
Dynamics and diversity in autophagy mechanisms: lessons from yeast
.
Nat. Rev. Mol. Cell Biol.
10
,
458
-
467
.
Nakayama
,
K.
and
Katoh
,
Y.
(
2018
).
Ciliary protein trafficking mediated by IFT and BBSome complexes with the aid of kinesin-2 and dynein-2 motors
.
J. Biochem.
163
,
155
-
164
.
Napolitano
,
G.
and
Ballabio
,
A.
(
2016
).
TFEB at a glance
.
J. Cell Sci.
129
,
2475
-
2481
.
Nilius
,
B.
and
Honoré
,
E.
(
2012
).
Sensing pressure with ion channels
.
Trends Neurosci.
35
,
477
-
486
.
Nishimura
,
T.
and
Tooze
,
S. A.
(
2020
).
Emerging roles of ATG proteins and membrane lipids in autophagosome formation
.
Cell Discov.
6
,
32
.
O'Neil
,
R. G.
and
Heller
,
S.
(
2005
).
The mechanosensitive nature of TRPV channels
.
Pflugers Arch.
451
,
193
-
203
.
Orhon
,
I.
,
Dupont
,
N.
,
Zaidan
,
M.
,
Boitez
,
V.
,
Burtin
,
M.
,
Schmitt
,
A.
,
Capiod
,
T.
,
Viau
,
A.
,
Beau
,
I.
,
Kuehn
,
E. W.
et al. 
(
2016
).
Primary-cilium-dependent autophagy controls epithelial cell volume in response to fluid flow
.
Nat. Cell Biol.
18
,
657
-
667
.
Panciera
,
T.
,
Azzolin
,
L.
,
Cordenonsi
,
M.
and
Piccolo
,
S.
(
2017
).
Mechanobiology of YAP and TAZ in physiology and disease
.
Nat. Rev. Mol. Cell Biol.
18
,
758
-
770
.
Papalazarou
,
V.
,
Zhang
,
T.
,
Paul
,
N. R.
,
Juin
,
A.
,
Cantini
,
M.
,
Maddocks
,
O. D. K.
,
Salmeron-Sanchez
,
M.
and
Machesky
,
L. M.
(
2020
).
The creatine-phosphagen system is mechanoresponsive in pancreatic adenocarcinoma and fuels invasion and metastasis
.
Nat. Metab.
2
,
62
-
80
.
Pavel
,
M.
,
Renna
,
M.
,
Park
,
S. J.
,
Menzies
,
F. M.
,
Ricketts
,
T.
,
Füllgrabe
,
J.
,
Ashkenazi
,
A.
,
Frake
,
R. A.
,
Lombarte
,
A. C.
,
Bento
,
C. F.
et al. 
(
2018
).
Contact inhibition controls cell survival and proliferation via YAP/TAZ-autophagy axis
.
Nat. Commun.
9
,
2961
.
Pedrozo
,
Z.
,
Criollo
,
A.
,
Battiprolu
,
P. K.
,
Morales
,
C. R.
,
Contreras-Ferrat
,
A.
,
Fernández
,
C.
,
Jiang
,
N.
,
Luo
,
X.
,
Caplan
,
M. J.
,
Somlo
,
S.
et al. 
(
2015
).
Polycystin-1 is a cardiomyocyte mechanosensor that governs L-Type Ca2+ channel protein stability
.
Circulation
131
,
2131
-
2142
.
Peña-Oyarzun
,
D.
,
Batista-Gonzalez
,
A.
,
Kretschmar
,
C.
,
Burgos
,
P.
,
Lavandero
,
S.
,
Morselli
,
E.
and
Criollo
,
A.
(
2020
).
New emerging roles of Polycystin-2 in the regulation of autophagy
.
Int. Rev. Cell Mol. Biol.
354
,
165
-
186
.
Pigino
,
G.
(
2021
).
Intraflagellar transport
.
Curr. Biol.
31
,
R530
-
R536
.
Pinheiro
,
D.
and
Bellaϊche
,
Y.
(
2018
).
Mechanical force-driven adherens junction remodeling and epithelial dynamics
.
Dev. Cell
47
,
391
.
Pocaterra
,
A.
,
Romani
,
P.
and
Dupont
,
S.
(
2020
).
YAP/TAZ functions and their regulation at a glance
.
J. Cell Sci.
133
,
jcs230425
.
Porter
,
K. M.
,
Jeyabalan
,
N.
and
Liton
,
P. B.
(
2014
).
MTOR-independent induction of autophagy in trabecular meshwork cells subjected to biaxial stretch
.
Biochim. Biophys. Acta (BBA) Mol. Cell Res.
1843
,
1054
-
1062
.
Praetorius
,
H. A.
(
2015
).
The primary cilium as sensor of fluid flow: new building blocks to the model. A review in the theme: cell signaling: proteins, pathways and mechanisms
.
Am. J. Physiol. Cell Physiol.
308
,
C198
-
C208
.
Qiao
,
S.
,
Dennis
,
M.
,
Song
,
X.
,
Vadysirisack
,
D. D.
,
Salunke
,
D.
,
Nash
,
Z.
,
Yang
,
Z.
,
Liesa
,
M.
,
Yoshioka
,
J.
,
Matsuzawa
,
S.-I.
et al. 
(
2015
).
A REDD1/TXNIP pro-oxidant complex regulates ATG4B activity to control stress-induced autophagy and sustain exercise capacity
.
Nat. Commun.
6
,
7014
.
Raghavan
,
V.
and
Weisz
,
O. A.
(
2016
).
Discerning the role of mechanosensors in regulating proximal tubule function
.
Am. J. Physiol. Renal Physiol.
310
,
F1
-
F5
.
Rashid
,
M. M.
,
Runci
,
A.
,
Russo
,
M. A.
and
Tafani
,
M.
(
2015
).
Muscle Lim Protein (MLP)/CSRP3 at the crossroad between mechanotransduction and autophagy
.
Cell Death Dis.
6
,
e1940
.
Roccio
,
F.
,
Claude-Taupin
,
A.
,
Botti
,
J.
,
Morel
,
E.
,
Codogno
,
P.
and
Dupont
,
N.
(
2021
).
Monitoring lipophagy in kidney epithelial cells in response to shear stress
.
Methods Cell Biol.
164
,
11
-
25
.
Romani
,
P.
,
Brian
,
I.
,
Santinon
,
G.
,
Pocaterra
,
A.
,
Audano
,
M.
,
Pedretti
,
S.
,
Mathieu
,
S.
,
Forcato
,
M.
,
Bicciato
,
S.
,
Manneville
,
J.-B.
et al. 
(
2019
).
Extracellular matrix mechanical cues regulate lipid metabolism through Lipin-1 and SREBP
.
Nat. Cell Biol.
21
,
338
-
347
.
Romani
,
P.
,
Valcarcel-Jimenez
,
L.
,
Frezza
,
C.
and
Dupont
,
S.
(
2021
).
Crosstalk between mechanotransduction and metabolism
.
Nat. Rev. Mol. Cell Biol.
22
,
22
-
38
.
Ross
,
E. J.
,
Gordon
,
E. R.
,
Sothers
,
H.
,
Darji
,
R.
,
Baron
,
O.
,
Haithcock
,
D.
,
Prabhakarpandian
,
B.
,
Pant
,
K.
,
Myers
,
R. M.
,
Cooper
,
S. J.
et al. 
(
2021
).
Three dimensional modeling of biologically relevant fluid shear stress in human renal tubule cells mimics in vivo transcriptional profiles
.
Sci. Rep.
11
,
14053
.
Santovito
,
D.
,
Egea
,
V.
,
Bidzhekov
,
K.
,
Natarelli
,
L.
,
Mourão
,
A.
,
Blanchet
,
X.
,
Wichapong
,
K.
,
Aslani
,
M.
,
Brunßen
,
C.
,
Horckmans
,
M.
et al. 
(
2020
).
Noncanonical inhibition of caspase-3 by a nuclear microRNA confers endothelial protection by autophagy in atherosclerosis
.
Sci. Transl. Med.
12
,
eaaz2294
.
Satir
,
P.
and
Christensen
,
S. T.
(
2007
).
Overview of structure and function of mammalian cilia
.
Annu. Rev. Physiol.
69
,
377
-
400
.
Sawa-Makarska
,
J.
,
Baumann
,
V.
,
Coudevylle
,
N.
,
von Bülow
,
S.
,
Nogellova
,
V.
,
Abert
,
C.
,
Schuschnig
,
M.
,
Graef
,
M.
,
Hummer
,
G.
and
Martens
,
S.
(
2020
).
Reconstitution of autophagosome nucleation defines Atg9 vesicles as seeds for membrane formation
.
Science
369
,
eaaz7714
.
Schwartz
,
L.
,
Abolhassani
,
M.
,
Pooya
,
M.
,
Steyaert
,
J.-M.
,
Wertz
,
X.
,
Israël
,
M.
,
Guais
,
A.
and
Chaumet-Riffaud
,
P.
(
2008
).
Hyperosmotic stress contributes to mouse colonic inflammation through the methylation of protein phosphatase 2A
.
Am. J. Physiol. Gastrointest. Liver Physiol.
295
,
G934
-
G941
.
Schwartz
,
L.
,
Guais
,
A.
,
Pooya
,
M.
and
Abolhassani
,
M.
(
2009
).
Is inflammation a consequence of extracellular hyperosmolarity?
J. Inflamm.
6
,
21
.
Sharifi
,
M. N.
,
Mowers
,
E. E.
,
Drake
,
L. E.
,
Collier
,
C.
,
Chen
,
H.
,
Zamora
,
M.
,
Mui
,
S.
and
Macleod
,
K. F.
(
2016
).
Autophagy promotes focal adhesion disassembly and cell motility of metastatic tumor cells through the direct interaction of Paxillin with LC3
.
Cell Rep.
15
,
1660
-
1672
.
Shen
,
H.-M.
and
Mizushima
,
N.
(
2014
).
At the end of the autophagic road: an emerging understanding of lysosomal functions in autophagy
.
Trends Biochem. Sci.
39
,
61
-
71
.
Shim
,
M. S.
,
Nettesheim
,
A.
,
Hirt
,
J.
and
Liton
,
P. B.
(
2020
).
The autophagic protein LC3 translocates to the nucleus and localizes in the nucleolus associated to NUFIP1 in response to cyclic mechanical stress
.
Autophagy
16
,
1248
-
1261
.
Shim
,
M. S.
,
Nettesheim
,
A.
,
Dixon
,
A.
and
Liton
,
P. B.
(
2021
).
Primary cilia and the reciprocal activation of AKT and SMAD2/3 regulate stretch-induced autophagy in trabecular meshwork cells
.
Proc. Natl. Acad. Sci. USA
118
,
e2021942118
.
Singh
,
R.
,
Kaushik
,
S.
,
Wang
,
Y.
,
Xiang
,
Y.
,
Novak
,
I.
,
Komatsu
,
M.
,
Tanaka
,
K.
,
Cuervo
,
A. M.
and
Czaja
,
M. J.
(
2009
).
Autophagy regulates lipid metabolism
.
Nature
458
,
1131
-
1135
.
Sinha
,
B.
,
Köster
,
D.
,
Ruez
,
R.
,
Gonnord
,
P.
,
Bastiani
,
M.
,
Abankwa
,
D.
,
Stan
,
R. V.
,
Butler-Browne
,
G.
,
Vedie
,
B.
,
Johannes
,
L.
et al. 
(
2011
).
Cells respond to mechanical stress by rapid disassembly of caveolae
.
Cell
144
,
402
-
413
.
Spasic
,
M.
and
Jacobs
,
C. R.
(
2017
).
Primary cilia: Cell and molecular mechanosensors directing whole tissue function
.
Semin. Cell Dev. Biol.
71
,
42
-
52
.
Spieth
,
P. M.
,
T.
,
Bluth
,
M.
,
Gama
,
De Abreu
,
A.
,
Bacelis
,
A. E.
,
Goetz
, and
R.
and
Kiefmann
, (
2014
).
Mechanotransduction in the lungs
.
Minerva Anestesiol.
80
,
933
-
941
.
Sun
,
L.
,
Zhao
,
M.
,
Liu
,
A.
,
Lv
,
M.
,
Zhang
,
J.
,
Li
,
Y.
,
Yang
,
X.
and
Wu
,
Z.
(
2018
).
Shear stress induces phenotypic modulation of vascular smooth muscle cells via AMPK/mTOR/ULK1-mediated autophagy
.
Cell. Mol. Neurobiol.
38
,
541
-
548
.
Sun
,
Z.
,
Costell
,
M.
and
Fässler
,
R.
(
2019
).
Integrin activation by talin, kindlin and mechanical forces
.
Nat. Cell Biol.
21
,
25
-
31
.
Swartz
,
M. A.
and
Lund
,
A. W.
(
2012
).
Lymphatic and interstitial flow in the tumour microenvironment: linking mechanobiology with immunity
.
Nat. Rev. Cancer
12
,
210
-
219
.
Takemura
,
G.
,
Miyata
,
S.
,
Kawase
,
Y.
,
Okada
,
H.
,
Maruyama
,
R.
and
Fujiwara
,
H.
(
2006
).
Autophagic degeneration and death of cardiomyocytes in heart failure
.
Autophagy
2
,
212
-
214
.
Tanabe
,
F.
,
Yone
,
K.
,
Kawabata
,
N.
,
Sakakima
,
H.
,
Matsuda
,
F.
,
Ishidou
,
Y.
,
Maeda
,
S.
,
Abematsu
,
M.
,
Komiya
,
S.
and
Setoguchi
,
T.
(
2011
).
Accumulation of p62 in degenerated spinal cord under chronic mechanical compression: functional analysis of p62 and autophagy in hypoxic neuronal cells
.
Autophagy
7
,
1462
-
1471
.
Tarbell
,
J. M.
and
Ebong
,
E. E.
(
2008
).
The endothelial glycocalyx: a mechano-sensor and -transducer
.
Sci. Signal.
1
,
pt8
.
Teng
,
B. T.
,
Pei
,
X. M.
,
Tam
,
E. W.
,
Benzie
,
I. F.
and
Siu
,
P. M.
(
2011
).
Opposing responses of apoptosis and autophagy to moderate compression in skeletal muscle
.
Acta Physiol.
201
,
239
-
254
.
Totaro
,
A.
,
Zhuang
,
Q.
,
Panciera
,
T.
,
Battilana
,
G.
,
Azzolin
,
L.
,
Brumana
,
G.
,
Gandin
,
A.
,
Brusatin
,
G.
,
Cordenonsi
,
M.
and
Piccolo
,
S.
(
2019
).
Cell phenotypic plasticity requires autophagic flux driven by YAP/TAZ mechanotransduction
.
Proc. Natl. Acad. Sci. USA
116
,
17848
-
17857
.
Tschumperlin
,
D. J.
,
Boudreault
,
F.
and
Liu
,
F.
(
2010
).
Recent advances and new opportunities in lung mechanobiology
.
J. Biomech.
43
,
99
-
107
.
Tschumperlin
,
D. J.
,
Ligresti
,
G.
,
Hilscher
,
M. B.
and
Shah
,
V. H.
(
2018
).
Mechanosensing and fibrosis
.
J. Clin. Invest.
128
,
74
-
84
.
Tse
,
J. M.
,
Cheng
,
G.
,
Tyrrell
,
J. A.
,
Wilcox-Adelman
,
S. A.
,
Boucher
,
Y.
,
Jain
,
R. K.
and
Munn
,
L. L.
(
2012
).
Mechanical compression drives cancer cells toward invasive phenotype
.
Proc. Natl. Acad. Sci. USA
109
,
911
-
916
.
Tuloup-Minguez
,
V.
,
Greffard
,
A.
,
Codogno
,
P.
and
Botti
,
J.
(
2011
).
Regulation of autophagy by extracellular matrix glycoproteins in HeLa cells
.
Autophagy
7
,
27
-
39
.
Tzima
,
E.
,
del Pozo
,
M. A.
,
Shattil
,
S. J.
,
Chien
,
S.
and
Schwartz
,
M. A.
(
2001
).
Activation of integrins in endothelial cells by fluid shear stress mediates Rho-dependent cytoskeletal alignment
.
EMBO J.
20
,
4639
-
4647
.
Uhler
,
C.
and
Shivashankar
,
G. V.
(
2017
).
Regulation of genome organization and gene expression by nuclear mechanotransduction
.
Nat. Rev. Mol. Cell Biol.
18
,
717
-
727
.
Ulbricht
,
A.
,
Eppler
,
F. J.
,
Tapia
,
V. E.
,
van der Ven
,
P. F. M.
,
Hampe
,
N.
,
Hersch
,
N.
,
Vakeel
,
P.
,
Stadel
,
D.
,
Haas
,
A.
,
Saftig
,
P.
et al. 
(
2013
).
Cellular mechanotransduction relies on tension-induced and chaperone-assisted autophagy
.
Curr. Biol.
23
,
430
-
435
.
van Helvert
,
S.
,
Storm
,
C.
and
Friedl
,
P.
(
2018
).
Mechanoreciprocity in cell migration
.
Nat. Cell Biol.
20
,
8
-
20
.
Venturini
,
V.
,
Pezzano
,
F.
,
Català Castro
,
F.
,
Häkkinen
,
H.-M.
,
Jiménez-Delgado
,
S.
,
Colomer-Rosell
,
M.
,
Marro
,
M.
,
Tolosa-Ramon
,
Q.
,
Paz-Lopez
,
S.
,
Valverde
,
M. A.
et al. 
(
2020
).
The nucleus measures shape changes for cellular proprioception to control dynamic cell behavior
.
Science
370
,
eaba2644
.
Verschuren
,
E. H. J.
,
Castenmiller
,
C.
,
Peters
,
D. J. M.
,
Arjona
,
F. J.
,
Bindels
,
R. J. M.
and
Hoenderop
,
J. G. J.
(
2020
).
Sensing of tubular flow and renal electrolyte transport
.
Nat. Rev. Nephrol.
16
,
337
-
351
.
Vining
,
K. H.
and
Mooney
,
D. J.
(
2017
).
Mechanical forces direct stem cell behaviour in development and regeneration
.
Nat. Rev. Mol. Cell Biol.
18
,
728
-
742
.
Vion
,
A.-C.
,
Kheloufi
,
M.
,
Hammoutene
,
A.
,
Poisson
,
J.
,
Lasselin
,
J.
,
Devue
,
C.
,
Pic
,
I.
,
Dupont
,
N.
,
Busse
,
J.
,
Stark
,
K.
et al. 
(
2017
).
Autophagy is required for endothelial cell alignment and atheroprotection under physiological blood flow
.
Proc. Natl. Acad. Sci. USA
114
,
E8675
-
E8684
.
Wang
,
N.
,
Butler
,
J. P.
and
Ingber
,
D. E.
(
1993
).
Mechanotransduction across the cell surface and through the cytoskeleton
.
Science
260
,
1124
-
1127
.
Wang
,
Z.
,
Shi
,
X.-Y.
,
Yin
,
J.
,
Zuo
,
G.
,
Zhang
,
J.
and
Chen
,
G.
(
2012
).
Role of autophagy in early brain injury after experimental subarachnoid hemorrhage
.
J. Mol. Neurosci.
46
,
192
-
202
.
Wang
,
L.
,
Luo
,
J. Y.
,
Li
,
B.
,
Tian
,
X. Y.
,
Chen
,
L. J.
,
Huang
,
Y.
,
Liu
,
J.
,
Deng
,
D.
,
Lau
,
C. W.
,
Wan
,
S.
et al. 
(
2016
).
Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow
.
Nature
540
,
579
-
582
.
Wang
,
X.
,
Zhang
,
Y.
,
Feng
,
T.
,
Su
,
G.
,
He
,
J.
,
Gao
,
W.
,
Shen
,
Y.
and
Liu
,
X.
(
2018
).
Fluid shear stress promotes autophagy in hepatocellular carcinoma cells
.
Int. J. Biol. Sci.
14
,
1277
-
1290
.
Wang
,
K.
,
Wei
,
Y.
,
Liu
,
W.
,
Liu
,
L.
,
Guo
,
Z.
,
Fan
,
C.
,
Wang
,
L.
,
Hu
,
J.
and
Li
,
B.
(
2019
).
Mechanical stress-dependent autophagy component release via extracellular nanovesicles in tumor cells
.
ACS Nano
13
,
4589
-
4602
.
Weinbaum
,
S.
,
Tarbell
,
J. M.
and
Damiano
,
E. R.
(
2007
).
The structure and function of the endothelial glycocalyx layer
.
Annu. Rev. Biomed. Eng.
9
,
121
-
167
.
Wolfenson
,
H.
,
Yang
,
B.
and
Sheetz
,
M. P.
(
2019
).
Steps in mechanotransduction pathways that control cell morphology
.
Annu. Rev. Physiol.
81
,
585
-
605
.
Xiang
,
W.
,
Jiang
,
T.
,
Hao
,
X.
,
Wang
,
R.
,
Yao
,
X.
,
Sun
,
K.
,
Guo
,
F.
and
Xu
,
T.
(
2019
).
Primary cilia and autophagy interaction is involved in mechanical stress mediated cartilage development via ERK/mTOR axis
.
Life Sci.
218
,
308
-
313
.
Xu
,
H.-G.
,
Yu
,
Y.-F.
,
Zheng
,
Q.
,
Zhang
,
W.
,
Wang
,
C.-D.
,
Zhao
,
X.-Y.
,
Tong
,
W.-X.
,
Wang
,
H.
,
Liu
,
P.
and
Zhang
,
X.-L.
(
2014
).
Autophagy protects end plate chondrocytes from intermittent cyclic mechanical tension induced calcification
.
Bone
66
,
232
-
239
.
Yan
,
L.
,
Vatner
,
D. E.
,
Kim
,
S.-J.
,
Ge
,
H.
,
Masurekar
,
M.
,
Massover
,
W. H.
,
Yang
,
G.
,
Matsui
,
Y.
,
Sadoshima
,
J.
and
Vatner
,
S. F.
(
2005
).
Autophagy in chronically ischemic myocardium
.
Proc. Natl. Acad. Sci. USA
102
,
13807
-
13812
.
Yan
,
Z.
,
Su
,
G.
,
Gao
,
W.
,
He
,
J.
,
Shen
,
Y.
,
Zeng
,
Y.
and
Liu
,
X.
(
2019
).
Fluid shear stress induces cell migration and invasion via activating autophagy in HepG2 cells
.
Cell Adh. Migr.
13
,
152
-
163
.
Yang
,
Q.
,
Li
,
X.
,
Li
,
R.
,
Peng
,
J.
,
Wang
,
Z.
,
Jiang
,
Z.
,
Tang
,
X.
,
Peng
,
Z.
,
Wang
,
Y.
and
Wei
,
D.
(
2016
).
Low shear stress inhibited endothelial cell autophagy through TET2 downregulation
.
Ann. Biomed. Eng.
44
,
2218
-
2227
.
Yao
,
P.
,
Zhao
,
H.
,
Mo
,
W.
and
He
,
P.
(
2016
).
Laminar shear stress promotes vascular endothelial cell autophagy through upregulation with Rab4
.
DNA Cell Biol.
35
,
118
-
123
.
Yap
,
A. S.
,
Duszyc
,
K.
and
Viasnoff
,
V.
(
2018
).
Mechanosensing and mechanotransduction at cell-cell junctions
.
Cold Spring Harb. Perspect. Biol.
10
,
a028761
.
Yu
,
J.
,
Bergaya
,
S.
,
Murata
,
T.
,
Alp
,
I. F.
,
Bauer
,
M. P.
,
Lin
,
M. I.
,
Drab
,
M.
,
Kurzchalia
,
T. V.
,
Stan
,
R. V.
and
Sessa
,
W. C.
(
2006
).
Direct evidence for the role of caveolin-1 and caveolae in mechanotransduction and remodeling of blood vessels
.
J. Clin. Invest.
116
,
1284
-
1291
.
Yu
,
Z.
,
Gong
,
X.
,
Yu
,
Y.
,
Li
,
M.
,
Liang
,
Y.
,
Qin
,
S.
,
Fulati
,
Z.
,
Zhou
,
N.
,
Shu
,
X.
,
Nie
,
Z.
et al. 
(
2019
).
The mechanical effects of CRT promoting autophagy via mitochondrial calcium uniporter down-regulation and mitochondrial dynamics alteration
.
J. Cell Mol. Med.
23
,
3833
-
3842
.
Yuan
,
P.
,
Hu
,
Q.
,
He
,
X.
,
Long
,
Y.
,
Song
,
X.
,
Wu
,
F.
,
He
,
Y.
and
Zhou
,
X.
(
2020
).
Laminar flow inhibits the Hippo/YAP pathway via autophagy and SIRT1-mediated deacetylation against atherosclerosis
.
Cell Death Dis.
11
,
141
.
Zemirli
,
N.
,
Boukhalfa
,
A.
,
Dupont
,
N.
,
Botti
,
J.
,
Codogno
,
P.
and
Morel
,
E.
(
2019
).
The primary cilium protein folliculin is part of the autophagy signaling pathway to regulate epithelial cell size in response to fluid flow
.
Cell Stress
3
,
100
-
109
.
Zhang
,
Y.
and
Liu
,
C.
(
2020
).
Autophagy and Hemorrhagic Stroke
.
Adv. Exp. Med. Biol.
1207
,
135
-
147
.
Zhang
,
Y.-B.
,
Li
,
S.-X.
,
Chen
,
X.-P.
,
Yang
,
L.
,
Zhang
,
Y.-G.
,
Liu
,
R.
and
Tao
,
L.-Y.
(
2008
).
Autophagy is activated and might protect neurons from degeneration after traumatic brain injury
.
Neurosci. Bull.
24
,
143
-
149
.
Zhang
,
J.-X.
,
Qu
,
X.-L.
,
Chu
,
P.
,
Xie
,
D.-J.
,
Zhu
,
L.-L.
,
Chao
,
Y.-L.
,
Li
,
L.
,
Zhang
,
J.-J.
and
Chen
,
S.-L.
(
2018
).
Low shear stress induces vascular eNOS uncoupling via autophagy-mediated eNOS phosphorylation
.
Biochim. Biophys. Acta (BBA) Mol. Cell Res.
1865
,
709
-
720
.
Zhang
,
X.
,
Jing
,
Y.
,
Qin
,
C.
,
Liu
,
C.
,
Yang
,
D.
,
Gao
,
F.
,
Yang
,
M.
,
Du
,
L.
and
Li
,
J.
(
2020
).
Mechanical stress regulates autophagic flux to affect apoptosis after spinal cord injury
.
J. Cell. Mol. Med.
24
,
12765
-
12776
.
Zhao
,
Y. G.
,
Liu
,
N.
,
Miao
,
G.
,
Chen
,
Y.
,
Zhao
,
H.
and
Zhang
,
H.
(
2018
).
The ER contact proteins VAPA/B interact with multiple autophagy proteins to modulate autophagosome biogenesis
.
Curr. Biol.
28
,
1234
-
1245.e4
.
Zhu
,
H.
,
Tannous
,
P.
,
Johnstone
,
J. L.
,
Kong
,
Y.
,
Shelton
,
J. M.
,
Richardson
,
J. A.
,
Le
,
V.
,
Levine
,
B.
,
Rothermel
,
B. A.
and
Hill
,
J. A.
(
2007
).
Cardiac autophagy is a maladaptive response to hemodynamic stress
.
J. Clin. Invest.
117
,
1782
-
1793
.
Zou
,
R.
,
Wu
,
S.
,
Wang
,
Y.
,
Kang
,
X.
,
Zhao
,
S.
,
Shi
,
H.
,
Zheng
,
D.
,
Gao
,
B.
,
Ma
,
S.
,
Niu
,
L.
et al. 
(
2021
).
Role of integrin-linked kinase in static compressive stress-induced autophagy via phosphatidylinositol 3 kinase in human periodontal ligament cells
.
Int. J. Mol. Med.
48
,
167
.

Competing interests

The authors declare no competing or financial interests.