Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure

Ujihara, Yoshihiro; Kanagawa, Motoi; Mohri, Satoshi; Takatsu, Satomi; Kobayashi, Kenzo; Toda, Tatsushi; Naruse, Keiji; Katanosaka, Yuki

doi:10.1038/s41467-019-13623-2

Cited by 31 publications

(37 citation statements)

References 66 publications

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“…Since non-muscle myosins have also been shown to stabilise high-molecular-weight protein complexes, such as actin scaffolds in the trans-Golgi while they are being sialylated, we postulated that a similar mechanism may regulate localisation of fibronectin and its consequent sialylation in the Golgi 33 , 34 . Furthermore, Golgi dysfunction in dystroglycanopathy was hypothesised as a contributing factor for the heterogeneity of these disorders in Fukutin-deficient mouse cardiac cells 35 . To examine this question, confocal and stimulated depletion emission (STED) microscopy were used to determine if fibronectin was mislocalised in the trans-Golgi of patient cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

FKRP-dependent glycosylation of fibronectin regulates muscle pathology in muscular dystrophy

Wood

Lin

et al. 2021

Nat Commun

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The muscular dystrophies encompass a broad range of pathologies with varied clinical outcomes. In the case of patients carrying defects in fukutin-related protein (FKRP), these diverse pathologies arise from mutations within the same gene. This is surprising as FKRP is a glycosyltransferase, whose only identified function is to transfer ribitol-5-phosphate to α-dystroglycan (α-DG). Although this modification is critical for extracellular matrix attachment, α-DG’s glycosylation status relates poorly to disease severity, suggesting the existence of unidentified FKRP targets. Here we reveal that FKRP directs sialylation of fibronectin, a process essential for collagen recruitment to the muscle basement membrane. Thus, our results reveal that FKRP simultaneously regulates the two major muscle-ECM linkages essential for fibre survival, and establishes a new disease axis for the muscular dystrophies.

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Section: Resultsmentioning

confidence: 99%

FKRP-dependent glycosylation of fibronectin regulates muscle pathology in muscular dystrophy

Wood

Lin

et al. 2021

Nat Commun

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“…Dystroglycan is a central component of the dystrophin-glycoprotein complex, where it functions as a transmembrane linker, anchoring the cytoskeleton to the extracellular matrix and plays a role in myocyte, sarcolemma and sarcomere stability 61,62 . Disruption of glycosylation has been associated with severe cardiac dysfunction in FKTN or LARGE1-deficient mice and with DCM (with mild to no skeletal muscle involvement) often in the context of homozygous or compound heterozygous variants [63][64][65] . We also found an enrichment of regulatory variants disrupting the expression of desmosomal genes (DSG2, DSC2, JUP, DSP) in which both missense and LoF variants have been reported to cause AVC, DCM and RCM, similar to patients in our cohort 66 .…”

Section: Discussionmentioning

confidence: 99%

Whole genome sequencing delineates regulatory and novel genic variants in childhood cardiomyopathy

Lesurf

Said

Akinrinade

et al. 2020

Preprint

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Cardiomyopathy (CMP) is a heritable genetic disorder. Protein-coding variants account for 20 to 30 percent of cases. The contribution of variants in noncoding DNA elements that regulate gene expression has not been explored. We performed whole genome sequencing (WGS) of 228 unrelated CMP families. Besides pathogenic protein coding variants in known CMP genes, 5% cases harbored rare loss of function variants in novel cardiac genes, with NRAP and FHOD3 being strong candidates. WGS also revealed a high burden of high risk variants in promoters and enhancers of CMP genes in an additional 20 percent cases (Odds ratio 2.14, 95 percent CI 1.60-2.86, p equals 5.26E-07 vs 1326 controls) with genes involved in alpha-dystroglycan glycosylation (FKTN, DTNA) and desmosomal signaling (DSC2, DSG2) specifically enriched for regulatory variants (False discovery rate less than 0.03). These findings were independently replicated in the Genomics England CMP cohort (n=1266). The functional effect of non-coding variants on transcription was functionally validated in patient myocardium and reporter assays in human cardiomyocytes, and that of novel gene variants in zebrafish knockouts. Our results show that functionally active variants in novel genes and in regulatory elements of CMP genes contribute strongly to the genomic etiology of childhood-onset CMP.

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“…Primary CMs were isolated from the ventricles of mice at aged stages (29-32 wks), as previously described (Ujihara et al, 2019). Briefly, the heart was excised and a cannula was inserted into the aorta.…”

Section: Isolation From Aged Micementioning

confidence: 99%

Transient induction of cell cycle promoter Fam64a improves cardiac function through regulating Klf15-dependent cardiomyocyte differentiation in mice

Hashimoto

Kodama

et al. 2021

Preprint

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The introduction of fetal or neonatal signatures such as cell cycle promoting genes into damaged adult hearts has been vigorously pursued as a promising strategy for stimulating proliferation and regeneration of adult cardiomyocytes, which normally cannot divide. However, cell division of cardiomyocytes requires preceding dedifferentiation with sarcomere disassembly and calcium dysregulation, which, in principle, compromises contractile function. To overcome this intrinsic dilemma, we explored the feasibility of optimizing the induction protocol of the cell cycle promoter in mice. As a model of this approach, we used Fam64a, a fetal-specific cardiomyocyte cell cycle promoter that we have recently identified. We first analyzed transgenic mice maintaining long-term cardiomyocyte-specific expression of Fam64a after birth, when endogenous expression was abolished. Despite having an enhanced proliferation of postnatal cardiomyocytes, these mice showed age-related cardiac dysfunction characterized by sustained cardiomyocyte dedifferentiation, which was reminiscent of the dilemma. Mechanistically, Fam64a inhibited glucocorticoid receptor-mediated transcriptional activation of Klf15, a key regulator that drives cardiomyocyte differentiation, thereby directing cardiomyocytes toward immature undifferentiated states. In contrast, transient induction of Fam64a in cryoinjured wildtype adult mice hearts improved functional recovery with augmented cell cycle activation of cardiomyocytes. These data indicate that optimizing the intensity and duration of the stimulant to avoid excessive cardiomyocyte dedifferentiation could pave the way toward developing efficient strategy for successful heart regeneration.

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Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure

Cited by 31 publications

References 66 publications

FKRP-dependent glycosylation of fibronectin regulates muscle pathology in muscular dystrophy

FKRP-dependent glycosylation of fibronectin regulates muscle pathology in muscular dystrophy

Whole genome sequencing delineates regulatory and novel genic variants in childhood cardiomyopathy

Transient induction of cell cycle promoter Fam64a improves cardiac function through regulating Klf15-dependent cardiomyocyte differentiation in mice

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