The caveolin–cavin system plays a conserved and critical role in mechanoprotection of skeletal muscle

Lo, Harriet P.; Nixon, Susan J.; Hall, Thomas; Cowling, Belinda S.; Ferguson, Charles; Morgan, Garry; Schieber, Nicole L.; Fernández‐Rojo, Manuel A.; Bastiani, Michele; Floetenmeyer, Matthias; Martel, Nick; Laporte, Jocelyn; Pilch, Paul F.; Parton, Robert G.

doi:10.1083/jcb.201501046

Cited by 136 publications

(138 citation statements)

References 59 publications

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“…However, whether incorporation of caveolae into the sarcolemmal membrane confers protection against membrane stress has not been tested. Consistent with previous reports showing increased susceptibility to acute membrane damage in the absence of caveolae (29,30), we showed that pressure overload-induced loss of caveolae compromises cardiomyocyte membrane integrity. Reminiscent of the effects seen with cardiac-specific Cav3 overexpression in mice (15), Fgf13 KO increased sarcolemmal caveolae density and membrane convolutions, thereby enhancing the reservoir of membrane available for mechanoprotection.…”

Section: Discussionsupporting

confidence: 81%

“…For instance, caveolae have been shown to protect against sarcolemmal damage in skeletal muscle during vigorous activity (29), and to mitigate endothelial cell membrane rupture during increased cardiac output (30). In cardiomyocytes, mechanical stretch was shown to increase cell membrane capacitance by recruiting subsarcolemmal caveolae to the plasma membrane (55).…”

Section: Discussionmentioning

confidence: 99%

“…Having shown that the increased caveolar density in Fgf13 KO myocytes enhanced cardioprotective signaling, we next tested whether the increased caveolar abundance also enhanced mechanoprotection by increasing the membrane reservoir available to buffer membrane tension. We used a hypoosmotic stress assay, which was previously shown to induce membrane rupture when caveolae were depleted (29). We observed that myocytes isolated from MCM and Fgf13 KO sham-operated mice displayed a similar degree of membrane blebbing (areas of rounded membrane protrusion) (Fig.…”

Section: Ko Of Fgf13 Enhances Mechanoprotection In Response To Ventrimentioning

confidence: 99%

“…First, we hypothesized that Fgf13 KO would phenocopy Cav3 overexpression, which was shown to mitigate TAC-induced pathological remodeling in part by preventing disruption of caveolae-associated macromolecular signaling complexes otherwise seen after TAC (28). Second, based on recent studies in skeletal muscle and endothelial cells highlighting that caveolae can serve as mechanoprotective membrane reservoirs that buffer increases in membrane tension (29,30), we hypothesized that increased caveolae abundance in Fgf13 KO myocytes ameliorated membrane damage caused by TAC-induced mechanical stretch. Overload.…”

Section: Fgf13 Ko Increases Sarcolemmal Caveolae Density In Cardiacmentioning

confidence: 99%

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Inducible Fgf13 ablation enhances caveolae-mediated cardioprotection during cardiac pressure overload

Wei

Sinden

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The fibroblast growth factor (FGF) homologous factor FGF13, a noncanonical FGF, has been best characterized as a voltage-gated Na + channel auxiliary subunit. Other cellular functions have been suggested, but not explored. In inducible, cardiac-specific Fgf13 knockout mice, we found-even in the context of the expected reduction in Na + channel current-an unanticipated protection from the maladaptive hypertrophic response to pressure overload. To uncover the underlying mechanisms, we searched for components of the FGF13 interactome in cardiomyocytes and discovered the complete set of the cavin family of caveolar coat proteins. Detailed biochemical investigations showed that FGF13 acts as a negative regulator of caveolae abundance in cardiomyocytes by controlling the relative distribution of cavin 1 between the sarcolemma and cytosol. In cardiac-specific Fgf13 knockout mice, cavin 1 redistribution to the sarcolemma stabilized the caveolar structural protein caveolin 3. The consequent increase in caveolae density afforded protection against pressure overload-induced cardiac dysfunction by two mechanisms: (i) enhancing cardioprotective signaling pathways enriched in caveolae, and (ii) increasing the caveolar membrane reserve available to buffer membrane tension. Thus, our results uncover unexpected roles for a FGF homologous factor and establish FGF13 as a regulator of caveolae-mediated mechanoprotection and adaptive hypertrophic signaling. (1), share a core domain with homology to canonical FGFs, but FHFs are not secreted, do not bind or activate FGF receptors, and do not function as growth factors (2). Instead, FHFs bind directly to voltage-gated Na + channels, modulating channel gating and trafficking (3, 4). Widely expressed in the brain (1), FHFs have been implicated in neurologic diseases such as spinocerebellar ataxia 27, caused by missense mutations in FGF14 that diminish Na + channel current, disrupt channel localization, and impair neuronal excitability (5-7).In addition to their broad distribution in the central nervous system, FHFs are expressed in the mammalian heart (1). Their roles in regulating cardiac function, however, have only been recently investigated. We showed that FGF13, the predominant FHF in rodent heart and a common transcript in human heart (8), directly binds to the C terminus of cardiac Na V 1.5 Na + channels, and thereby regulates current density and conduction velocity by affecting channel gating and surface expression (9). Similarly, mutations that disrupt interaction between Na V 1.5 and FGF12, the major human cardiac FHF, have been linked to lifethreatening arrhythmia syndromes (8, 10). In addition to regulating Na + channels, FHFs can modulate voltage-gated Ca 2+ channels (11, 12). Fgf13 knockdown in adult rodent ventricular cardiomyocytes decreased Ca V 1.2 current density, perturbed Ca V 1.2 localization at the dyad, and thereby affected Ca 2+ -induced Ca 2+ release (11). Because previous studies were conducted in cultured cardiomyocytes, however, the in vivo roles for FHFs in ...

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Ko Of Fgf13 Enhances Mechanoprotection In Response To Ventrimentioning

confidence: 99%

Section: Fgf13 Ko Increases Sarcolemmal Caveolae Density In Cardiacmentioning

confidence: 99%

See 2 more Smart Citations

Inducible Fgf13 ablation enhances caveolae-mediated cardioprotection during cardiac pressure overload

Wei

Sinden

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…This basic structure has been referred to as a quantal unit (9). However, sub-quantal oligomeric structures of Cav1 have been described in the PM (9), as well as caveolar clusters formed by multiple caveolae in close, diffraction-limited proximity (10) or as larger rosette structures (11).…”

Section: Edited By Dennis R Voelkermentioning

confidence: 99%

Phosphatidylserine dictates the assembly and dynamics of caveolae in the plasma membrane

Hirama

Das

Yang

et al. 2017

Journal of Biological Chemistry

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Edited by Dennis R. VoelkerCaveolae are bulb-shaped nanodomains of the plasma membrane that are enriched in cholesterol and sphingolipids. They have many physiological functions, including endocytic transport, mechanosensing, and regulation of membrane and lipid transport. Caveola formation relies on integral membrane proteins termed caveolins (Cavs) and the cavin family of peripheral proteins. Both protein families bind anionic phospholipids, but the precise roles of these lipids are unknown. Here, we studied the effects of phosphatidylserine (PtdSer), phosphatidylinositol 4-phosphate (PtdIns4P), and phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P 2 ) on caveolar formation and dynamics. Using live-cell, single-particle tracking of GFP-labeled Cav1 and ultrastructural analyses, we compared the effect of PtdSer disruption or phosphoinositide depletion with caveola disassembly caused by cavin1 loss. We found that PtdSer plays a crucial role in both caveola formation and stability. Sequestration or depletion of PtdSer decreased the number of detectable Cav1-GFP puncta and the number of caveolae visualized by electron microscopy. Under PtdSer-limiting conditions, the co-localization of Cav1 and cavin1 was diminished, and cavin1 degradation was increased. Using rapamycin-recruitable phosphatases, we also found that the acute depletion of PtdIns4P and PtdIns (4,5)P 2 has minimal impact on caveola assembly but results in decreased lateral confinement. Finally, we show in a model of phospholipid scrambling, a feature of apoptotic cells, that caveola stability is acutely affected by the scrambling. We conclude that the predominant plasmalemmal anionic lipid PtdSer is essential for proper Cav clustering, caveola formation, and caveola dynamics and that membrane scrambling can perturb caveolar stability.

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Identification of Caveolae-Associated Protein 4 Autoantibodies as a Biomarker of Immune-Mediated Rippling Muscle Disease in Adults

et al. 2022

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Immune-mediated rippling muscle disease (iRMD) is a rare myopathy characterized by wavelike muscle contractions (rippling) and percussion-or stretch-induced muscle mounding. A serological biomarker of this disease is lacking.OBJECTIVE To describe a novel autoantibody biomarker of iRMD and report associated clinicopathological characteristics. DESIGN, SETTING, AND PARTICIPANTSThis retrospective cohort study evaluated archived sera from 10 adult patients at tertiary care centers at the Mayo Clinic, Rochester, Minnesota, and Brigham & Women's Hospital, Boston, Massachusetts, who were diagnosed with iRMD by neuromuscular specialists in 2000 and 2021, based on the presence of electrically silent percussion-or stretch-induced muscle rippling and percussion-induced rapid muscle contraction with or without muscle mounding and an autoimmune basis. Sera were evaluated for a common biomarker using phage immunoprecipitation sequencing. Myopathology consistent with iRMD was documented in most patients. The median (range) follow-up was 18 (1-30) months. EXPOSURES Diagnosis of iRMD.MAIN OUTCOMES AND MEASURES Detection of a common autoantibody in serum of patients sharing similar clinical and myopathological features.RESULTS Seven male individuals and 3 female individuals with iRMD were identified (median [range] age at onset, 60 [18-76] years). An IgG autoantibody specific for caveolae-associated protein 4 (cavin-4) was identified in serum of patients with iRMD using human proteome phage immunoprecipitation sequencing. Immunoassays using recombinant cavin-4 confirmed cavin-4 IgG seropositivity in 8 of 10 patients with iRMD. Results for healthy and disease-control individuals (n = 241, including myasthenia gravis and immune-mediated myopathies) were cavin-4 IgG seronegative. Six of the 8 individuals with cavin-4 IgG were male, and the median (range) age was 60 (18-76) years. Initial symptoms included rippling of lower limb muscles in 5 of 8 individuals or all limb muscles in 2 of 8 sparing bulbar muscles, fatigue in 9 of 10, mild proximal weakness in 3 of 8, and isolated myalgia in 1 of 8, followed by development of diffuse rippling. All patients had percussion-induced muscle rippling and half had percussion-or stretch-induced muscle mounding. Four of the 10 patients had proximal weakness. Plasma creatine kinase was elevated in all but 1 patient. Six of the 10 patients underwent malignancy screening; cancer was detected prospectively in only 1. Muscle biopsy was performed in 7 of the 8 patients with cavin-4 IgG; 6 of 6 specimens analyzed immunohistochemically revealed a mosaic pattern of sarcolemmal cavin-4 immunoreactivity. Three of 6 patients whose results were seropositive and who received immunotherapy had complete resolution of symptoms, 1 had mild improvement, and 2 had no change. CONCLUSIONS AND RELEVANCEThe findings indicate that cavin-4 IgG may be the first specific serological autoantibody biomarker identified in iRMD. Depletion of cavin-4 expression in muscle biopsies of patients with iRMD suggests the potential role ...

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The caveolin–cavin system plays a conserved and critical role in mechanoprotection of skeletal muscle

Abstract: The caveolar membrane microdomain plays an integral role in stabilizing the muscle fiber surface in mice and zebrafish.

Cited by 136 publications

References 59 publications

Inducible Fgf13 ablation enhances caveolae-mediated cardioprotection during cardiac pressure overload

Inducible Fgf13 ablation enhances caveolae-mediated cardioprotection during cardiac pressure overload

Phosphatidylserine dictates the assembly and dynamics of caveolae in the plasma membrane

Identification of Caveolae-Associated Protein 4 Autoantibodies as a Biomarker of Immune-Mediated Rippling Muscle Disease in Adults

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