Dysregulation of NRAP degradation by KLHL41 contributes to pathophysiology in nemaline myopathy

Jirka, Caroline; Pak, Jasmine H; Grosgogeat, Claire A; Marchetii, Michael Mario; Gupta, Vandana

doi:10.1093/hmg/ddz078

Cited by 28 publications

(29 citation statements)

References 61 publications

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“…including Nrap, Fhod3, Enah, and Flnc, as well as the non-muscle myosins Myh9 and Myh10, which have been postulated as components of "pre-myofibrils" laid down as scaffolds before mature muscle-specific myosins are assembled ( Fig. 2d) [22][23][24][25][26][27] . Multiple transcription factors were enriched in transient myonuclei, including both known drivers of skeletal muscle differentiation (Ifrd1, Nfat5, Mef2a) [28][29][30] and numerous TFs with no previous associations in muscle (Ell, Creb5, Zfp697) (Extended Data Fig.…”

Section: Mainmentioning

confidence: 99%

Single-nucleus RNA-seq identifies transcriptional heterogeneity in multinucleated skeletal myofibers

Petrany

Swoboda

Sun

et al. 2020

Preprint

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While the majority of cells contain a single nucleus, cell types such as trophoblasts, osteoclasts, and skeletal myofibers require multinucleation. One advantage of multinucleation can be the assignment of distinct functions to different nuclei, but comprehensive interrogation of transcriptional heterogeneity within multinucleated tissues has been challenging due to the presence of a shared cytoplasm. Here, we utilized single-nucleus RNA-sequencing (snRNA-seq) to determine the extent of transcriptional diversity within multinucleated skeletal myofibers. Nuclei from mouse skeletal muscle were profiled across the lifespan, which revealed the emergence of distinct myonuclear populations in postnatal development and their reactivation in aging muscle. Our datasets also provided a platform for discovery of novel genes associated with rare specialized regions of the muscle cell, including markers of the myotendinous junction and functionally validated factors expressed at the neuromuscular junction. These findings reveal that myonuclei within syncytial muscle fibers possess distinct transcriptional profiles that regulate muscle biology.

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Section: Mainmentioning

confidence: 99%

Single-nucleus RNA-seq identifies transcriptional heterogeneity in multinucleated skeletal myofibers

Petrany

Swoboda

Sun

et al. 2020

Preprint

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“…The same changes in KLHL41 expression were found in the 3× dosage group (Additional file 1: Figure S7A). It was also recently reported that nebulin-related anchoring protein, NRAP, is associated with sarcomeric dysregulation and is regulated by KLHL41 [65]. Following Z-disk AAV treatment, CTRL TC muscles trended toward higher expression while CTRL EDL muscles experienced a significant increase in NRAP expression ( Fig.…”

Section: Alterations In Nebulin Chaperone Protein Klhl41 and Downstrementioning

confidence: 57%

“…KLHL41 was also reported to regulate nebulin-related anchoring protein, NRAP [65]. Interestingly, when this protein is removed in KLHL41-deficient muscle, the myopathy phenotypes are reversed [65]. Quantification of the expression of these two proteins found that CTRL muscles produce more of both proteins in AAV-treated muscles (Fig.…”

Section: Changes In Regulatory Proteins Associated With Nemaline Myopmentioning

confidence: 87%

“…Both overexpression and loss of KLHL41 have been shown to cause nemaline myopathylike phenotypes [19,87], implying that its regulation is critical to sarcomeric structure. KLHL41 was also reported to regulate nebulin-related anchoring protein, NRAP [65]. Interestingly, when this protein is removed in KLHL41-deficient muscle, the myopathy phenotypes are reversed [65].…”

Section: Changes In Regulatory Proteins Associated With Nemaline Myopmentioning

confidence: 99%

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Expressing a Z-disk nebulin fragment in nebulin-deficient mouse muscle: effects on muscle structure and function

Kolb

Crudele

et al. 2020

Skeletal Muscle

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Background: Nebulin is a critical thin filament-binding protein that spans from the Z-disk of the skeletal muscle sarcomere to near the pointed end of the thin filament. Its massive size and actin-binding property allows it to provide the thin filaments with structural and regulatory support. When this protein is lost, nemaline myopathy occurs. Nemaline myopathy causes severe muscle weakness as well as structural defects on a sarcomeric level. There is no known cure for this disease. Methods: We studied whether sarcomeric structure and function can be improved by introducing nebulin's Z-disk region into a nebulin-deficient mouse model (Neb cKO) through adeno-associated viral (AAV) vector therapy. Following this treatment, the structural and functional characteristics of both vehicle-treated and AAV-treated Neb cKO and control muscles were studied.Results: Intramuscular injection of this AAV construct resulted in a successful expression of the Z-disk fragment within the target muscles. This expression was significantly higher in Neb cKO mice than control mice. Analysis of protein expression revealed that the nebulin fragment was localized exclusively to the Z-disks and that Neb cKO expressed the nebulin fragment at levels comparable to the level of full-length nebulin in control mice. Additionally, the Z-disk fragment displaced full-length nebulin in control mice, resulting in nemaline rod body formation and a worsening of muscle function. Neb cKO mice experienced a slight functional benefit from the AAV treatment, with a small increase in force and fatigue resistance. Disease progression was also slowed as indicated by improved muscle structure and myosin isoform expression. Conclusions: This study reveals that nebulin fragments are well-received by nebulin-deficient mouse muscles and that limited functional benefits are achievable.

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“…Nebulette and nebulin are homologous in function and have similar protein structure but far more studies have been conducted on dissecting nebulin and its role in skeletal sarcomere assembly and maintenance, which is discussed in this review [22]. While no chaperones have been identified for nebulin folding, NRAP, KLHL41 (skeletal muscle-specific factor), and KLHL40 bind to nebulin and prevent the giant from aggregating or degrading [23][24][25][26]. The binding of these chaperones may result in the localization of nebulin to the Z-disc.…”

Section: Thin Filament Assembly In the Sarcomerementioning

confidence: 99%

Assembly and Maintenance of Sarcomere Thin Filaments and Associated Diseases

Prill

Dawson

2020

IJMS

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Sarcomere assembly and maintenance are essential physiological processes required for cardiac and skeletal muscle function and organism mobility. Over decades of research, components of the sarcomere and factors involved in the formation and maintenance of this contractile unit have been identified. Although we have a general understanding of sarcomere assembly and maintenance, much less is known about the development of the thin filaments and associated factors within the sarcomere. In the last decade, advancements in medical intervention and genome sequencing have uncovered patients with novel mutations in sarcomere thin filaments. Pairing this sequencing with reverse genetics and the ability to generate patient avatars in model organisms has begun to deepen our understanding of sarcomere thin filament development. In this review, we provide a summary of recent findings regarding sarcomere assembly, maintenance, and disease with respect to thin filaments, building on the previous knowledge in the field. We highlight debated and unknown areas within these processes to clearly define open research questions.

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Dysregulation of NRAP degradation by KLHL41 contributes to pathophysiology in nemaline myopathy

Cited by 28 publications

References 61 publications

Single-nucleus RNA-seq identifies transcriptional heterogeneity in multinucleated skeletal myofibers

Single-nucleus RNA-seq identifies transcriptional heterogeneity in multinucleated skeletal myofibers

Expressing a Z-disk nebulin fragment in nebulin-deficient mouse muscle: effects on muscle structure and function

Assembly and Maintenance of Sarcomere Thin Filaments and Associated Diseases

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