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Mitochondrial dysfunction in Nemaline myopathy type 6

ABSTRACT: Nemaline Myopathy type 6 (NEM6) is a congenital myopathy caused by variants in KBTBD13...

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Soleus

DISEASE(S): Nemaline Myopathy 6

SUBMITTER: Rianne Baelde

LAB HEAD: Rianne Baelde

PROVIDER: PXD071917 | Pride | 2026-06-29

REPOSITORIES: Pride

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			Action	DRS
	23P0107_01_1_8482.d.zip	Other
	23P0107_02_1_8492.d.zip	Other
	23P0107_03_1_8489.d.zip	Other
	23P0107_04_1_8485.d.zip	Other
	23P0107_05_1_8497.d.zip	Other

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Publications

Nicotinamide riboside prevents mitochondrial dysfunction in nemaline myopathy type 6.

Baelde Rianne J RJ Vonk Leander A LA Nollet Edgar E EE Galli Ricardo A RA Monteiro Alexcia Fortes AF Bastu Sultan S Das Bornale B van Weeghel Michel M Schomakers Bauke V BV Vinten Kasper T KT van den Berg Marloes M van der Velden Jolanda J Houtkooper Riekelt H RH Voermans Nicol C NC Malfatti Edoardo E Ottenheijm Coen A C CAC de Winter Josine M JM

Human molecular genetics 20260601 12

Nemaline Myopathy type 6 (NEM6) is a congenital myopathy caused by variants in Kelch-repeat-and-BTB-(POZ)-Domain-Containing-13 (KBTBD13). The majority of the NEM6 patients harbor the Dutch founding variant KBTBD13R408C (c.1222C > T, p.Arg408Cys) and experience skeletal muscle weakness and sarcomere-based hypercontractility. Histological characterization of NEM6 patient biopsies by NADH staining shows the presence of cores, suggesting mitochondrial dysfunction. We aimed to elucidate the role of m ...[more]

PMID: 42323895

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Dysregulation of muscle myosin biochemical states in X-linked myotubular myopathy

Project description:Pathogenic variants in MTM1 are associated with a severe, congenital muscle disorder called X-linked myotubular myopathy. Here, we aimed to assess the effect of mavacamten (myosin ATPase inhibitor) treatment in a mouse model for X-linked myotubular myopathy (Mtm1-KO) using the global untargeted proteomics approach. We used skeletal muscle tissue from Mtm1-KO mice and from WT mice, both treated and not treated with mavacamten.

2025-10-31 | PXD068387 | Pride

In vivo and in vitro investigations of heterozygous nebulin knock-out mice reveal similarities with mild human form of nemaline myopathy

Project description:This SuperSeries is composed of the following subset Series: GSE36741: In vivo and in vitro investigations of heterozygous nebulin knock-out mice reveal similarities with mild human form of nemaline myopathy [miRNA] GSE36743: In vivo and in vitro investigations of heterozygous nebulin knock-out mice reveal similarities with mild human form of nemaline myopathy [mRNA] Refer to individual Series

2012-09-01 | E-GEOD-36745 | biostudies-arrayexpress

Loss of Hectd1 disrupts muscle sarcomere assembly and causes combined desmin-nemaline myopathy

Project description:The sarcomere is the muscle contractile unit, whose assembly and disassembly are intimately linked to changes in myofiber size and function. Mutations in sarcomeric proteins are common causes of myopathies, ranging from severe neonatal to adult-onset forms. Here, we identify HECTD1 as an E3 ubiquitin ligase necessary for sarcomere maintenance. We show that silencingHectd1 in myotubesreduces the levels of proteins critical for sarcomere integrity including a-actin, titin, troponins, tropomyosins, and several myosin heavy chain isoforms. We further establish that Hectd1 ubiquitylates and stabilizes the molecular chaperones KLHL40/41, that when dysfunctional destabilize nebulin and other sarcomere thin filament proteins (causing nemaline myopathy). Consequently, skeletal muscle-specific Hectd1 knockout mice (Hectd1 mKO) show progressive muscle weakness, exercise intolerance, and unresolved tissue remodeling. Molecular and histological analysis of Hectd1 mKO muscle revealed subsarcolemmal storage of the scaffold protein desmin, mitochondrial abnormalities, and severe sarcomere disorganization. This work uncovers Hectd1 as an E3 ligase critical for sarcomere assembly, and a novel diagnostic gene for myopathy with features of nemaline and desmin myopathy.

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Nemaline myopathy mouse model

Project description:The aim of this study was to investigate the molecular mechanisms implicated in this mouse model of nemaline myopathy, and to further compare the molecular disease response in different skeletal muscles. For this purpose, snap frozen skeletla muscle specimens from wild type and transgenic for alpha tropomyosin slow mice were studied. Five different muscle types were used (diaphragm, plantaris, extensor digitorum longus, tibialis anterior, gastrocnemus). Mice were sacrificed between 7 and 10 months. RNA pools from 3-5 animals were created and each pool was hybridized to a U74Av2 Affymetrix GeneChip. Datasets from 36 GeneChips were included in this study. Keywords: disease mouse model analysis

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Effect of Mavacamten on skeletal muscle fibre proteome in nemaline myopathy

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Identifying secondary processes implicated in nemaline myopathy pathophysiology

Project description:Nemaline myopathy (NM) is a genetically and clinically heterogeneous disease that is diagnosed based on the presence of nemaline rods on skeletal muscle biopsy. While NM has typically been classified by causative genes, disease severity or prognosis cannot be predicted well. The common pathological endpoint of nemaline rods (despite diverse genetic causes) and an unexplained range of muscle weakness suggests that shared secondary processes contributed to the pathogenesis of NM. We speculated that these processes could be identified through a proteome wide interrogation utilizing a mouse model of severe NM in combination with pathway validation and structural/functional analyses. A proteomic analysis was performed using skeletal muscle tissue from the Neb cKO, KI.Acta1H40Y, and TgACTA1D286G mouse models of nemaline myopathy as compared to their respective wild-type counterparts (Neb WT, WT.Acta1H40Y, and C57) to identify pathophysiologically relevant biological processes that might impact disease severity or provide new treatment targets. Downstream analyses utilizing Scaffold, RStudio, and Ingenuity Pathway Analysis identified mitochondrial dysfunction and stress-related signaling as being enriched in NM mouse datasets. Pathway validation revealed that proteins in mitochondrial and stress-related signaling pathways aggregated in NM muscle in a severity dependent manner and an increase in protein content was generally associated with more severe disease. Structural and functional mitochondrial analyses revealed that mitochondrial dysfunction also grades with disease severity. RCI measured by respirometry, ATP/ADP/phosphate content, and mitochondrial transmembrane potential were affected in a severity dependent manner with the Neb cKOs being the most abnormal, KI.Acta1H40Y being mildly affected, and the TgACTA1D286G being minimally affected. These studies identify mitochondrial dysfunction as a secondary process impacting disease severity in NM.

2025-05-06 | PXD042201 | Pride

FOXK2 in Skeletal Muscle Development: A New Pathogenic Gene for Congenital Myopathy with Ptosis

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Mus musculus

Project description:Nemaline myopathy mouse model

| PRJNA93519 | ENA

Comparison of genes regulated in P0 Klhl40 WT and KO skeletal muscle

Project description:Nemaline myopathy (NM) is a congenital myopathy that can result in lethal muscle dysfunction and is thought to be a disease of the sarcomere thin filament. Recently, several proteins of unknown function have been implicated in NM, and their role in the disease remains unresolved. Here, we demonstrate that loss of a muscle-specific protein, Klhl40, results in a nemaline-like myopathy in mice that closely phenocopies the muscle abnormalities observed KLHL40 deficient patients. We show that Klhl40 dynamically localizes to the sarcomere I-band and A-band and binds to Nebulin (Neb), a protein frequently implicated in NM, as well as a putative thin filament protein, Lmod3. Klhl40 belongs to the BTB-BACK-Kelch (BBK) family of proteins, some of which have been previously shown to promote degradation of their substrates. In contrast, we find that Klhl40 promotes stability of Neb and Lmod3 and blocks Lmod3 ubiquitination. Accordingly, loss of Klhl40 reduces Neb and Lmod3 protein in skeletal muscle of mice and KLHL40 deficient patients. Because loss of sarcomere thin filament proteins is a frequent cause of NM, our data establishes a possible molecular basis for NM in KLHL40 deficient patients by establishing a novel pro-stability function of Klhl40 for Neb and Lmod3.

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