government site. Zuzek A, Fan JD, Spaeth CS, & Bittner GD (2013). HHS Vulnerability Disclosure, Help Many organisms and tissues display the ability to heal and regenerate as needed for normal physiology and as a result of pathogenesis. Without adequate remodeling, the plasma membrane protein and lipid composition would change dramatically, particularly after repeat injuries, and no longer function as in its pre-injury state. The antioxidant requirement for plasma membrane repair in skeletal muscle. Federal government websites often end in .gov or .mil. Translocation of existing lipid species to the site of injury provides a mechanism to recruit and activate protein machinery. Mechanical feedback between membrane tension and dynamics. Semin Cell Dev Biol. This signaling function may occur due to the activity of the repair protein EHD2, which accumulates at the site of membrane injury and is thought to play a role in shaping membrane dynamics (Daumke et al., 2007; Demonbreun et al., 2016; Marg et al., 2012). These structural changes to lipids are both necessary for repair and potentially pathogenic if left uncorrected (Sreetama et al., 2018). One such mechanism for this may be mediated by the protein MG53. Shear stress on the plasma membrane also results in the dissociation of the negative regulator RhoGDI and its binding partner Rho (Shao et al., 2018). Bethesda, MD 20894, Web Policies Other cells acquire specialized functions as they mature. Visualizing cytoplasmic flow during single-cell wound healing in Stentor coeruleus. Cells as part of multicellular systems rarely act alone, instead having ways to signal to start and complete simple to quite complex interactions. This is due to their lack of integration into the membrane under normal lipid packing conditions. Careers, Unable to load your collection due to an error. Another critical shared feature is a set of highly-specialized teeth. Plasma membrane lipids and proteins interact with the extracellular matrix (ECM) and the cortical actin network, both of which provide sources of tension that support the structure of the membrane. 2022 May 15;23(10):5525. doi: 10.3390/ijms23105525. PA is then used to create other phospholipids including PI, PC, PS, and PE, through the use of the DAG backbone. Stem cell extracellular vesicles: extended messages of regeneration, Annual review of pharmacology and toxicology. Further, the addition of new membrane by increased calcium-triggered exocytosis also decreases membrane tension and is required for plasma membrane repair (Togo et al., 2000). Curr Biol. Cell Regen. As discussed above, sphingolipids in the plasma membrane are an important regulator of plasma membrane repair. The radiation could prevent the DNA from replicating correctly. Due to the differences in the three-dimensional conformations of membrane lipids, a change in their distribution changes the lipid packing density in a given lipid domain. The physical properties of the plasma membrane are governed in large part by the effect of lipid interactions at the population level. This is notable because it is hypothesized that a beneficial role of decreasing membrane fluidity is preventing the spread of harmful lipid hydroperoxides, which likely form in the oxidative environment near the site of injury (Braughler & Hall, 1992; Hall, Wang, Miller, Cebak, & Hill, 2018). Delivery of membrane (i.e. Small GTPases, such as Rho family members, associate with biological membranes via lipid modifications (ten Klooster & Hordijk, 2007); however, selectivity for the plasma membrane is regulated through the polybasic domain comprised of a cluster of positively charged amino acids (Do Heo et al., 2006; Maxwell, Zhou, & Hancock, 2018). PIP2 also accumulates at the site of membrane injury (Demonbreun et al., 2016; Vaughan et al., 2014). lipids) is one of the roles proposed for lysosome-mediated repair (Andrews et al., 2014; McNeil, 2002). 8600 Rockville Pike sharing sensitive information, make sure youre on a federal Bouter A, Gounou C, Brat R, Tan S, Gallois B, Granier T, Brisson AR. The role of lipids during plasma membrane repair goes far beyond a passive role in vesicle-mediated delivery of membrane lipids. Defour A, Van der Meulen JH, Bhat R, Bigot A, Bashir R, Nagaraju K, & Jaiswal JK (2014). Such a role of CLIC/GEEC-mediated endocytosis in membrane remodeling is also supported by the observation that CLIC/GEEC is immediately activated in response to decreased membrane tension and has the capacity to turn over large amounts of plasma membrane (Thottacherry et al., 2018). Failure or delay in these processes, as in chronic inflammatory conditions and conditions of regenerative deficit would lead to aberrant tissue remodeling resulting in fibrotic or adipogenic replacement of the lost tissue. The .gov means its official. Use the force: membrane tension as an organizer of cell shape and motility. Lipids act as signaling molecules through their ability to directly bind or otherwise alter the activity or localization of target proteins (Figure 2B, ,C).C). Clipboard, Search History, and several other advanced features are temporarily unavailable. Lysosomes are involved with various cell processes. FOIA Stem cell medicine brings a new paradigm to modern medicine which has relied heavily on medicine or surgery. J.K.J. The radiation could damage the DNA so badly that the cell dies. Accumulation of GRAF1 at the repair site occurs 2 minutes after injury, supporting its potential role in membrane remodeling following resealing. Inositol is bound to the phosphate group in this phospholipid. The physical and molecular mechanisms by which a cell can heal membrane ruptures and rebuild damaged or missing cellular structures remain poorly understood. Plasma membrane lipids are routinely interconverted as a means to maintain lipid homeostasis and for lipid-mediated signaling. In addition to their structural role in shaping the physical properties of the plasma membrane, lipids also play an important signaling role in maintaining plasma membrane integrity. Careers. Cambridge (MA): Harvard Stem Cell Institute; 2008. See this image and copyright information in PMC. Calcium also initiates lipid signaling after plasma membrane injury by activating phospholipases, such as phospholipase C (PLC). At the population level, the composition of lipids in a membrane can result in formation of signaling platforms that can change the properties of an entire membrane, enabling the cell to finely tune tension, shape, and rigidity. While the local accumulation of proteins such as annexins acts to stabilize the structurally unstable membrane after injury, remodeling of the membrane itself can achieve a similar outcome. As MG53 interacts with the plasma membrane in a cholesterol-dependent manner ((Zhu et al., 2012); see Section 4), its extracellular role may involve a mode of action similar to poloxamer 188, where it inserts within membranes in a disordered lipid environment. Repair of injured plasma membrane by rapid Ca2+-dependent endocytosis. (D) The lipid make-up of the plasma membrane constantly changes. This cytoskeletal assembly is regulated by Rho GTPase activity, which triggers F-actin accumulation at the site of injury. The spatial arrangement of lipids at the plasma membrane is not only important for GTPase recruitment, but also for their activity. Thus, while increase in lipid mobility following plasma membrane injury is associated with successful repair, excessive lipid mobility leading to membrane instability is detrimental to the repair process. The tension forces acting on the plasma membrane are generally applied by three sources: the difference in hydrostatic pressure between the cell interior and extracellular space, the cortical cytoskeletal network, and the extracellular matrix to which the cell is attached (Gauthier, Masters, & Sheetz, 2012; Kozlov & Chernomordik, 2015) (Figure 2B). 2023 Feb 28;24(5):4707. doi: 10.3390/ijms24054707. Gauthier NC, Masters TA, & Sheetz MP (2012). Accessibility The basement membrane of the basal cells attaches via hemidesmosomes to the underlying Bowman's layer, while anchoring fibrils pass through . Eukaryotic cells have been confronted throughout their evolution with potentially lethal plasma membrane injuries, including those caused by osmotic stress, by infection from bacterial toxins and parasites, and by mechanical and ischemic stress. sharing sensitive information, make sure youre on a federal Scheffer LL, Sreetama SC, Sharma N, Medikayala S, Brown KJ, Defour A, & Jaiswal JK (2014). As a library, NLM provides access to scientific literature. Phospholipids in particular show inter-leaflet heterogeneity. Plasma membrane damage caused by listeriolysin O is not repaired through endocytosis of the membrane pore. All RightsReserved. Ribosome damage: Damage to ribosomal and cellular proteins such as protein misfolding, Leading to apoptotic enzyme activation. Disruption of the cell plasma membrane is a commonplace occurrence in many mechanically challenging, biological environments. While it is unclear whether caveolae can provide structural assistance to the damaged membrane in the context of a large membrane injury (as opposed to sub-injury threshold stress, (Sinha et al., 2011)), caveolae may still provide a signaling function during the repair process. This is especially important for membrane signaling functions as the liquid-ordered domains often serve to aggregate membrane-associated proteins (Cebecauer et al., 2018). Lysosome fusion is required for the process of repair (Reddy, Caler, & Andrews, 2001). The radiation could pass through the cell without damaging the DNA. What's found inside a cell. 2022 Dec 14;10(12):3256. doi: 10.3390/biomedicines10123256. Johnson JL, Erickson JW, & Cerione RA (2012). Constitutive fusion of biosynthetic vesicles is a major mechanism for delivery of new lipids and proteins, which helps to build and maintain the plasma membrane. It has since become evident that in addition to resealing, remodeling of the plasma membrane through vesicle fusion (exocytosis), vesicle internalization (endocytosis), and shedding (ectocytosis) also contribute to the repair process (reviewed in (Horn & Jaiswal, 2018)). Arun SN, Xie D, Howard AC, Zhong Q, Zhong X, McNeil PL, & Bollag WB (2013). The reduction in membrane tension is likely due directly to the addition of phospholipids to reduced lipid packing, as well as due in part to the cytoskeletal remodeling associated with vesicular transport at the plasma membrane. This phase represents restoration of the barrier function of the plasma membrane; however, cells must still undergo a membrane remodeling phase due to the presence of cytoskeletal as well as other repair proteins and lipids that accumulate during the repair process. cell, in biology, the basic membrane-bound unit that contains the fundamental molecules of life and of which all living things are composed. Rather than these roles being separated from each other, they overlap significantly such that one can easily be an extension of the other. Microfluidic guillotine reveals multiple timescales and mechanical modes of wound response in Stentor coeruleus. In bacterial and plant cells, a cell wall is attached to the plasma membrane on its outside surface. sharing sensitive information, make sure youre on a federal These examples illustrate the far-reaching consequence of lipid movement on structural stability of the plasma membrane and its ability to successfully repair. Federal government websites often end in .gov or .mil. In this case, cholesterol actually increases the fluidity among these lipids, which prevents them from forming a gel-like phase that is incompatible with the overall fluid nature of the plasma membrane (Krause & Regen, 2014). Myofiber injury in zebrafish was found to cause rapid loss of PIP2, followed by restoration to pre-injury levels by 30 seconds post-injury (Middel et al., 2016). Front Cell Dev Biol. 2023 Apr 4;122(7):1355-1363. doi: 10.1016/j.bpj.2023.03.001. Quantification of membrane tension after injury to fibroblasts demonstrated that a minimum tension force was reached by approximately 30 seconds post-injury, but tension was fully restored by 80 seconds post-injury (Togo et al., 2000). While PA mediates targeting to the membrane, Rac1 activity depends on PIP3, suggesting multiple roles for signaling lipids in GTPase activity after repair. F-actin accumulation is also responsible for providing support to the newly resealed membrane, restoring tension, and preventing subsequent injury. doi: 10.1042/BSR20220765. PLD-mediated activation of PI5K relies on the formation of PA, which itself is able to determine the spatial localization of PI5K as well as cause its activation (Roach et al., 2012). Poloxamer 188 facilitates the repair of alveolus resident cells in ventilator-injured lungs, American journal of respiratory and critical care medicine. Examples of self-repairing cells. Cell damage can be reversible or irreversible. The vast majority of biochemical assembly and break down processeseven by the most complex organismsoccur within cells. Epub 2015 Oct 19. Epub 2012 Jul 9. ESCRT machinery is required for plasma membrane repair. Rac1, a Rho family GTPase required for repair (Verboon & Parkhurst, 2015), forms nanoclusters at sites enriched in PA and PIP3, whose roles in regulating Rac1 appear to be non-overlapping (Maxwell et al., 2018). Modeling membrane shaping by proteins: Focus on EHD2 and NBAR domains. Regulation of Rac1 translocation and activation by membrane domains and their boundaries, Stressing caveolae new role in cell mechanics, Membrane cytoskeleton: PIP2 pulls the strings, The FluidMosaic Model of Membrane Structure: Still relevant to understanding the structure, function and dynamics of biological membranes after more than 40 years, Biochimica et Biophysica Acta (BBA)-Biomembranes. It must repair itself, first by stopping the loss of cytoplasm, and then regenerate by rebuilding structures that were damaged or lost. Verweij FJ, Revenu C, Arras G, Dingli F, Loew D, Pegtel DM, Zimmermann P (2019). Given their ability to traverse away from the site of synthesis (Verweij et al., 2019), the EVs generated during plasma membrane injury may activate both local and distant tissue regeneration responses needed for repair. In addition to working on their own, lipids also interact with proteins to coordinate these processes. Biosci Rep. 2023 Feb 27;43(2):BSR20220765. 2008 Mar 10;180(5):905-14. doi: 10.1083/jcb.200708010. Unauthorized use of these marks is strictly prohibited. Marg A, Schoewel V, Timmel T, Schulze A, Shah C, Daumke O, & Spuler S (2012). "Think of a . It can also be produced by methylation of existing PE, while PE can be produced by the decarboxylation of PS. The tight packing, along with the preference of cholesterol to intercalate the acyl chains of sphingomyelin creates the liquid-ordered membrane domains, such as the so-called lipid rafts (Van Meer et al., 2008) (Figure 2C). Phospholipids and sphingolipids are connected by the head group choline, found on both PC and sphingomyelin (SM). If the damage is beyond repair, the cell will normally send itself into apoptosis, ensuring that it will not pass on its damaged DNA. 2021 Sep 29;9:753625. doi: 10.3389/fcell.2021.753625. During the G1 stage, the cell prepares for division by increasing its mass. During regeneration, sphingolipids such as sphingosine 1-phosphate (S1P) are known for their growth promoting effect on tissue resident stem cells (Calise et al., 2012; Nojima, Freeman, Gulbins, & Lentsch, 2015). Inherent plasticity and microfracture toughening mechanisms work together to prevent antlers from breaking. Eukaryotic cells have been confronted throughout their evolution with potentially lethal plasma membrane injuries, including those caused by osmotic stress, by infection from bacterial toxins and parasites, and by mechanical and ischemic stress. Sarcolemmal repair is a slow process and includes EHD2, Effect of oxidative stress on membrane structure: small-angle X-ray diffraction analysis. It must repair itself, first by stopping the loss of cytoplasm, and then regenerate by rebuilding structures that were damaged or lost. Calise S, Blescia S, Cencetti F, Bernacchioni C, Donati C, & Bruni P (2012). Schematic representation of the structural features of the protein families implicated in membrane repair. Minetti C, Sotgia F, Bruno C, Scartezzini P, Broda P, Bado M, Donati MA (1998). In this review, we will focus on the role of lipids during plasma membrane repair by discussing their functions as both structural and signaling molecules. An actin-dependent annexin complex mediates plasma membrane repair in muscle. Sood P, Lin A, Yan C, McGillivary R, Diaz U, Makushok T, Nadkarni AV, Tang SKY, Marshall WF. Here the sugar (oligosaccharide) moiety faces the extracellular space interacting with other cells and extracellular ligands required for processes such as signaling, cell adhesion or intercellular interactions. Learn whats new on AskNature by signing up for our e-newsletter. This process is more efficient when GTPases and their regulatory proteins (which are themselves regulated by lipids) are clustered (Ligeti, Dagher, Hernandez, Koleske, & Settleman, 2004). In response to increased stress on the plasma membrane, caveolae have been proposed to act as mechanosensors, buffering membrane tension in response to mechanical stress (Cheng et al., 2015; Sinha et al., 2011). Calcium can activate proteins directly, and ultimately is the initiator of many downstream repair pathways. A decrease in membrane tension precedes successful cell-membrane repair. As muscle fibers have strong interfiber connections, muscle injuries may manifest both as shearing of the membrane from increased membrane tension and strain, as well as ripping of plasma membrane regions from fiber retraction or hypercontraction. Muscle fibers are subject to huge variations in membrane tension, due to their contractile activity. This form of membrane remodeling maintains lipid homeostasis and plasma membrane functionality. Trends Cell Biol. See this image and copyright information in PMC. Cells respond to mechanical stress by rapid disassembly of caveolae. Dr. Norma Andrews overviews the mechanisms of cellular plasma membrane repair. Negative membrane curvature catalyzes nucleation of endosomal sorting complex required for transport (ESCRT)-III assembly. As these features change dynamically, tension forces experienced by the plasma membrane are not static and the cells ability to respond to them appropriately allows for essential functions such as change in morphology, movement, adhering to new substrates, cell division, and membrane fusion. Below we describe the biochemical signaling role of lipids in facilitating plasma membrane repair. Bi G-Q, Alderton JM, & Steinhardt RA (1995). Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy. The site is secure. Calcium entry after plasma membrane injury is required for repair. Slabodnick M, Prevo B, Gross P, Sheung J, Marshall W. J Vis Exp. Shed microvesicles containing streptolysin-O have been shown to also contain annexins A1 and A6 (219). Survival from bacterial pore-forming toxins utilizes both exocytic and endocytic responses. This involves a series of distinct, but mutually dependent stages including inflammation, regeneration, and remodeling of the tissue (Gurtner, Werner, Barrandon, & Longaker, 2008). Collective evidence reveals membrane repair employs primitive yet robust molecular machinery, such as vesicle fusion and contractile rings, processes evolutionarily honed for simplicity and success. Palmitate-mediated disruption of the endoplasmic reticulum decreases intracellular vesicle motility. Importantly, sequestration of cholesterol alone increased PLD activity, supporting the idea that transient increase in lipid fluidity after membrane injury may be required for PLD-mediated signaling. How skin heals is a good example of the role of cellular processes. MG53 (40) shows diffuse enrichment at injury sites within 2 s of membrane injury in a calcium-independent manner (150). These same processes also work to dynamically control membrane fluidity by regulating the distribution of phospholipids, sphingolipids, and cholesterol in the membrane. The plasma membrane has a unique lipid composition that helps distinguish its structural and functional properties from the other internal membrane-bound compartments. McDade JR, Archambeau A, & Michele DE (2014). In mammalian cells the majority of cellular cholesterol is found in the plasma membrane, where it can make up to 50% of lipid content (Van Meer, Voelker, & Feigenson, 2008). Evidence suggests these pores are removed both by endosomal degradative pathways (123, 164, 280) and exosomal shedding (14, 118, 136). In. The plasma membrane itself forms the barrier responsible for the hydrostatic pressure experienced by the cell, while the cortical actin cytoskeleton, focal adhesions, and extracellular matrix regulate the structural tension (Burridge & Guilluy, 2016; Gauthier et al., 2012). The physical and molecular mechanisms by which a cell can heal membrane ruptures and rebuild damaged or missing cellular structures remain poorly understood. Inflammatory exudates provide insights into the regulation of the first stage of wound repair inflammation. It also works extracellularly to improve repair of injured muscle and other cells (Gushchina et al., 2017; Weisleder et al., 2012). Matsuo H, Chevallier J, Mayran N, Le Blanc I, Ferguson C, Faur J, Sadoul R (2004). Additionally, in contrast to PS, which recruits proteins directly involved in repair, DAG appears to recruit signaling proteins such as protein kinase C (PKC) (Vaughan et al., 2014; Zuzek, Fan, Spaeth, & Bittner, 2013). Alterations in Phosphatidylcholine Metabolism of StretchInjured Cultured Rat Astrocytes. doi: 10.3791/50848. Given their integral role in forming the structural backbone of the membrane, lipids are ideally placed to act as damage sensors, initiating early signaling that sets the stage for subsequent repair machinery. Roach AN, Wang Z, Wu P, Zhang F, Chan RB, Yonekubo Y, Du G (2012). eCollection 2021. Like the exterior walls of a house, the . For example, the dynamic arrangement of lipids in the plasma membrane as discussed above, and the electrostatic or chemical changes in lipids due to enzymatic activity of lipid modifying enzymes rapidly affect lipids themselves as well as the target proteins in the plasma membrane (Figure 2B, ,C).C). Role of phosphatidylinositol 4, 5-bisphosphate in regulating EHD2 plasma membrane localization. Compared with cytosolic antioxidants, which can be detrimental to repair (Spaeth et al., 2012), vitamin E is membrane-localized and could therefore allow for the local buildup of oxidized lipids at the site of injury while preventing the global spread of lipid oxidation. It is unclear what role, if any, that IP3 may have in repair, but its role in calcium signaling and the fact that injured cells secrete IP3 for hours post-injury (Lamb et al., 1997) suggest a possible signaling role in repair that may extend beyond the process of membrane resealing, which needs further investigation. Bacterial pore-forming, What might membrane injury to muscle fibers look like? Bethesda, MD 20894, Web Policies While intracellular MG53 is a redox-sensitive protein capable of facilitating vesicle aggregation, it is proposed to have multiple functions during membrane repair. Tailored protection against plasmalemmal injury by annexins with different Ca2+ sensitivities, Sphingolipids and the formation of sterol-enriched ordered membrane domains, Plasma membrane repair is mediated by Ca2+-regulated exocytosis of lysosomes. Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis and plasma membrane repair. This preferential association between different lipids results in an important feature of the plasma membrane its transverse and lateral heterogeneity. Changing the head group attached to the DAG backbone creates different phospholipid species, which include phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidylglycerol (PG), and PA (Oropeza, 2017) (Figure 1B). The physical and molecular mechanisms by which a cell can heal membrane ruptures and rebuild damaged or missing cellular structures remain poorly understood. Yasuda S, Townsend D, Michele DE, Favre EG, Day SM, & Metzger JM (2005). Each of these pathways that facilitate repair through membrane remodeling also alter the local composition and distribution of plasma membrane lipids in healthy cells (van Meer, 1989) (Figure 2D). From PA, cells generate DAG, or cytidine diphosphate-DAG (CDP-DAG), which serve as inputs into the phospholipid biosynthetic pathways (Figure 1A, ,B).B). FOIA Membrane-stabilizing copolymers confer marked protection to dystrophic skeletal muscle in vivo, Molecular Therapy-Methods & Clinical Development. These enzymes initiate signaling through the generation of new lipid species, providing an added spatial, as well as a temporal component to lipid signaling, helping to more precisely coordinate the repair response. With an abundance of uncharged (zwitterionic) lipids and smaller amounts of neutral and anionic glycosphingolipids in the outer leaflet, and the negatively charged phosphatidylserine, phosphatidic acid and phosphatidylinositol within the inner leaflet, there exists a charge differential between the two plasma membrane leaflets (Steck & Lange, 2018; Zachowski, 1993). Spatial arrangement of lipids is also known to regulate Rho family GTPase activity (see Section 4.3). Lipids contribute to cellular physiology at both an individual and population level. Nakamura M, Hui J, Stjepi V, Parkhurst SM. Arp2/3-mediated F-actin formation controls regulated exocytosis in vivo. Membrane stabilization by modified steroid offers a potential therapy for muscular dystrophy due to dysferlin deficit, Transverse distribution of plasma membrane bilayer cholesterol: Picking sides. Influx of calcium from the extracellular space, as well as locally increased oxidation, both trigger lipid signaling that is required for repair. Once membrane tension is restored, the poloxamer compound is forced out of the outer membrane leaflet (Houang, Sham, Bates, & Metzger, 2018). Int J Mol Sci. Requirement for annexin A1 in plasma membrane repair, Repairing a torn cell surface: make way, lysosomes to the rescue, Plasma membrane disruption: repair, prevention, adaptation, Annual review of cell and developmental biology, Coping with the inevitable: how cells repair a torn surface membrane, Biochemistry of lipids, lipoproteins and membranes. As structural components of the plasma membrane, lipids are responsible for contributing to membrane tension, rigidity, and overall shape. Epub 2008 Oct 9. Cells (whether entire unicellular organisms or parts of multicellular living systems) grow, metabolize nutrients (that is, chemically transform them), produce proteins and enzymes, replicate, and move. The https:// ensures that you are connecting to the Two-way traffic on the road to plasma membrane repair. PIP2 accumulation was observed as early as 4 seconds in mouse myofibers; however, it continued to accumulate even 1 minute post-injury suggesting a role in the later stages of repair (Demonbreun et al., 2016). The https:// ensures that you are connecting to the While this mechanism outlines how ESCRT proteins assemble, the lipid signaling that determines the appropriate spatial localization relative to the membrane injury in order to limit wound expansion has not been elucidated. ESCRT assembly for membrane shedding is activated by the calcium-dependent ALG-2 protein, which then recruits its interacting partner ALIX leading to subsequent recruitment of the remaining complex members (Scheffer et al., 2014). Self-repair: Our bodies are packages within packages. Middel V, Zhou L, Takamiya M, Beil T, Shahid M, Roostalu U, Nienhaus GU (2016). Endocytosis can also occur at sites of membrane invagination known as caveolae, and caveolae internalization has been implicated in membrane repair (Corrotte et al., 2013). Membrane lipids: where they are and how they behave. These roles of lipids in plasma membrane repair include both a structural role and a signaling role. Patients with muscular dystrophy are more susceptible to injury from eccentric stretch (216), with studies in mouse models suggesting susceptibility to injury can escalate with multiple insults (53). Each of these lipids contributes their own qualities that affect the structural and signaling characteristics of the plasma membrane (Nicolson, 2014).