![]() ![]() CAVIN4 expression also increased in response to injury-induced muscle regeneration via activation of the extracellular-signal-regulated kinase pathway ( Tagawa et al., 2008). In mature mammalian skeletal muscle, CAVIN4 localized to the sarcolemmal membrane ( Bastiani et al., 2009). The functional role of Cavin4 in skeletal muscle has not been studied in detail. However, the presence of these CAVIN4 variants and others in the Genome Aggregation Database ( ), suggest that these mutations should also be considered as potential disease modifiers rather than primary disease-causing mutations ( Szabadosova et al., 2018). Mutations in CAVIN4 have been implicated in dilated cardiomyopathy in humans, and expression of these mutations in rat cardiomyocytes led to reduced RhoA activity, lower mRNA levels of hypertrophy markers, and smaller myocyte size ( Rodriguez et al., 2011). Muscle-specific CAVIN4 was originally identified as a CAVIN2-interacting protein in cardiomyocytes, where its overexpression led to cardiac defects in mice ( Ogata et al., 2008). It is also apparent that while embryonic T-tubules possess caveolar morphology and components, mature T-tubules in mammals lose their caveolae as the membrane is remodeled ( Parton et al., 1997 Schiaffino et al., 1977). A loss of CAV3 in mice caused T-tubule abnormalities, although T-tubules still develop ( Galbiati et al., 2001). ![]() ![]() Further studies showed similarities between T-tubules and caveolae in their sensitivity to cholesterol manipulation ( Carozzi et al., 2000). Early morphological studies showed striking chains of interconnected caveolae in developing embryonic muscle ( Ishikawa, 1968) these networks were positive for both the T-tubule marker DHPR and CAV3 ( Lee et al., 2002 Parton et al., 1997). The mature T-system has a unique lipid and protein composition distinct from the sarcolemma how this is generated and maintained is not yet clear. Additional roles for caveolae and caveolar components in skeletal muscle have been derived from studies of the transverse-tubule (T-tubule) system, a crucial feature of the muscle surface comprising an extensive network of tubules that penetrate deep into the muscle interior, allowing the propagation of action potentials to facilitate synchronized calcium release (reviewed in Franzini-Armstrong, 2018). Consistent with early electron microscope studies proposing that caveolae function as membrane reservoirs in response to increasing membrane tension ( Dulhunty and Franzini-Armstrong, 1975 Lee and Schmid-Schönbein, 1995), evidence for caveolae protecting the cell surface against mechanical damage has now been well documented in skeletal muscle ( Lo et al., 2015 Seemann et al., 2017 Sinha et al., 2011), endothelial cells ( Cheng et al., 2015), and the zebrafish notochord ( Lim et al., 2017). In skeletal muscle, caveolae can account for as much as 50% of the muscle fiber surface ( Lo et al., 2015). Muscle-specific CAVIN4 (muscle-restricted coiled coil ) is not required for caveola formation but may play a role in caveolar morphology ( Bastiani et al., 2009 Ogata et al., 2014 Ogata et al., 2008). Caveolae-associated protein 1 (CAVIN1 previously known as PTRF) is widely expressed and essential for caveolae formation, acting in concert with CAV1 (in nonmuscle cells) and CAV3 (in muscle cells) to generate caveolae ( Hill et al., 2008 Liu et al., 2008). ![]() More recently, the cavin family of caveolae-associated coat proteins (CAVIN1–CAVIN4) have been described ( Bastiani et al., 2009 Hansen et al., 2009 Hill et al., 2008 McMahon et al., 2009). Caveolins were the first structural component of caveolae identified Caveolin-1 (CAV1) and Caveolin-3 (CAV3) are essential for caveola formation in nonmuscle and muscle cells, respectively ( Drab et al., 2001 Fra et al., 1995 Hagiwara et al., 2000 Way and Parton, 1995). The formation of caveolae requires a coordinated assembly involving two essential protein components, the caveolins and cavins. Caveolae are plasma membrane invaginations that are abundant in many mammalian cells and implicated in a number of fundamental cellular processes, including mechanoprotection and mechanosensation, lipid homeostasis, endocytosis, and regulation of signaling pathways (reviewed in Parton, 2018). ![]()
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