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

Abstract

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 ...

Knockout of the X‐linkedFgf13in the hypothalamic paraventricular nucleus impairs sympathetic output to brown fat and causes obesity

“…Using a validated antibody against FGF13 (20,36), we observed abundant Fgf13 expression in the heart and the brain (Fig. 5A), where we and others (12,19,20,40,42) previously documented Fgf13 expression and function. Moreover, we saw a relative reduction in FGF13 protein in Fgf13 +/2 mice compared with WT in both heart and brain, confirming efficacy of the heterozygous knockout.…”

“…We and others have characterized Fgf13 effects on cardiac function (13,14,20,(39)(40)(41), neuronal migration during development (19), epileptogenesis (12), and ion channel trafficking and targeting in the axon initiation segment of cultured hippocampal neurons (42), yet gene ablation studies have not been employed to investigate roles for Fgf13 in metabolism, despite multiple studies reporting differential expression in adipose tissue in response to alterations in diet and in different obesogenic genetic backgrounds (21)(22)(23)(24)(25). To begin to investigate metabolic functions we generated a global Fgf13 knockout mouse model on a C57BL/6J background.…”

“…Rather, their best characterized function is as modulators of voltage-gated Na + channels (Na V s) (9), and mutations that affect their Na V modulatory ability have been identified in cardiac arrhythmias and neurologic diseases such as Brugada syndrome, autosomal dominant cerebral ataxia, and epilepsy (10)(11)(12). Beyond regulation of Na V s, FGF13, encoded by Fgf13 on the X chromosome, can regulate other voltage-gated ion channels (13,14) and appears to affect a number of other cellular processes and contribute to physiology or disease states, including cancer (15), hypertrichosis (16), smooth and skeletal muscle cell development (17,18), microtubule stabilization in developing neurons (19), and protection from mechanical stress in cardiomyocytes by regulation of caveolae (20). These observations suggest that the full complement of FGF13 functions is not fully defined.…”

FGF13 Is a Novel Regulator of NF-κB and Potentiates Pathological Cardiac Hypertrophy

“…The role of FGF13 in regulating cardiac function, however, has only been recently investigated. Conditional knockout of FGF13 in murine hearts increases arrhythmia susceptibility and exhibits an increased abundance of caveolae in cardiomyocytes and thereby ameliorates pathological myocardial hypertrophy ( Wang et al., 2017 ; Wei et al., 2017 ). Nevertheless, the importance of FGF13 in cardiomyocytes remains to be explored.…”

Deciphering role of FGFR signalling pathway in pancreatic cancer

“…Overexpression of FGF-19 did not affect the cell proliferation, but inhibited cell migration, invasion and attachment via stimulation of FGFR4 in pancreatic cancer cells. 68 Loss of Ffg15 (human homolog, FGF19) deficiency impairs liver regeneration in mice.…”