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Effect of Mavacamten on skeletal muscle fibre proteome in nemaline myopathy

ABSTRACT: Nemaline myopathy (NM) is a genetic muscle disorder, notably caused by mutations in the NEB gene (NEB-NM). Here we investigated the efficacy of a four-week Mavacamten (myosin ATPase inhibitor) treatment using a NEB-NM mouse model. After the four weeks, soleus muscles were extracted, muscle fibres were isolated, and a global untargeted proteomics approach was employed. As presented in the data set, a lot of various proteins were affected by the treatment.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Skeletal Muscle Fiber, Skeletal Muscle Cell

SUBMITTER: Michael Wierer

LAB HEAD: Julien Ochala

PROVIDER: PXD051963 | Pride | 2025-10-14

REPOSITORIES: Pride

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Publications

Myosin ATPase inhibition fails to rescue the metabolically dysregulated proteome of nebulin-deficient muscle.

Laitila Jenni J Seaborne Robert A E RAE Ranu Natasha N Kolb Justin S JS Wallgren-Pettersson Carina C Witting Nanna N Vissing John J Vilchez Juan Jesus JJ Zanoteli Edmar E Palmio Johanna J Huovinen Sanna S Granzier Henk H Ochala Julien J

The Journal of physiology 20240831 20

Nemaline myopathy (NM) is a genetic muscle disease, primarily caused by mutations in the NEB gene (NEB-NM) and with muscle myosin dysfunction as a major molecular pathogenic mechanism. Recently, we have observed that the myosin biochemical super-relaxed state was significantly impaired in NEB-NM, inducing an aberrant increase in ATP consumption and remodelling of the energy proteome in diseased muscle fibres. Because the small-molecule Mavacamten is known to promote the myosin super-relaxed stat ...[more]

PMID: 39216086

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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

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.

2014-04-08 | GSE56570 | GEO

NAD Depletion in Skeletal Muscle does not Compromise Muscle Function or Accelerate Aging

Project description:NAD is a ubiquitous electron carrier essential for energy metabolism and the post translational modification of numerous regulatory proteins. Perturbation of NAD metabolism is considered detrimental to health, with NAD depletion commonly thought to promote aging. However, the extent to which cellular NAD concentration can be decreased without deleterious repercussions is unclear. We generated a mouse model where nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ biosynthesis is disrupted in adult skeletal muscle. The resulting 85% decrease in muscle NAD+ abundance was associated with preserved tissue integrity and functionality, as demonstrated by its unchanged morphology, contractility, and exercise tolerance. This lack of defects was corroborated by intact mitochondrial respiratory capacity and unaffected muscle transcriptomic and proteomic profiles. Furthermore, lifelong NAD depletion did not accelerate muscle aging or impair whole-body metabolism. Collectively, these findings indicate that NAD depletion does not contribute to age related declines in skeletal muscle function.

2025-04-23 | PXD061221 | Pride

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

2014-04-08 | E-GEOD-56570 | biostudies-arrayexpress

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

The effect of Nebulin-Deficiency on Skeletal Muscle

Project description:Nebulin is a giant filamentous protein that is coextensive with the actin filaments of the skeletal muscle sarcomere. Nebulin mutations are the main cause of nemaline myopathy (NEM), with typical NEM adult patients having low expression of nebulin, yet the roles of nebulin in adult muscle remain poorly understood. To establish nebulin’s functional roles in adult muscle we performed studies on a novel conditional nebulin KO (Neb cKO) mouse model in which nebulin deletion was driven by the muscle creatine kinase (MCK) promotor. Neb cKO mice are born with high nebulin levels in their skeletal muscle but within weeks after birth nebulin expression rapidly falls to barely detectable levels Surprisingly, a large fraction of the mice survives to adulthood with low nebulin levels (<5% of control), contain nemaline rods, and undergo fiber-type switching towards oxidative types. These microarrays investigate the changes in gene expression when nebulin is deficient. Two skeletal muscle groups were studied: Quadriceps (which is markedly smaller in the Neb cKO mice relative to control) and Soleus (which is not significantly smaller in the Neb cKO relative to control). Six biological replicates for each muscle group were selected; all are age-matched males.

2015-06-25 | E-GEOD-70213 | biostudies-arrayexpress

The effect of Nebulin-Deficiency on Skeletal Muscle

2015-06-25 | GSE70213 | GEO

Global proteomics reveals distinct muscle adaptations to menstrual cycle phase-based sprint interval training in endurance-trained females

Project description:Advances in mass-spectrometry (MS)-based technologies have leveraged our understanding of protein-wide adaptations in human skeletal muscle in response to exercise. However, there is a lack of such data in females, particularly pertaining to already trained females and menstrual cycle phase-based sprint interval training (SIT) despite its efficacy and popularity. Here, we present a comprehensive global proteome analysis of skeletal muscle adaptations to high-frequency SIT during different menstrual cycle phases in endurance-trained females. We randomized 49 eumenorrheic females to either high-frequency SIT in the follicular (FB) or luteal phase (LB) over one menstrual cycle comprising eight sessions of 6×30-s all-out efforts. MS-proteomics, covering 4155 proteins after filtering, revealed notable differences in muscle adaptations to phase-based SIT. LB suppressed mitochondrial pathways of the tricarboxylic acid cycle and electron transport chain while enriching ribosomal complexes. Conversely, FB enriched filament organization and skeletal system development. Mitochondrial repression during LB was linked to reduced O2max, whereas exercise capacity improved in FB only. Our findings show that menstrual cycle phase-based high-frequency SIT induces distinct protein-wide muscle adaptations and affects phenotype in endurance-trained eumenorrheic females.

2025-08-21 | PXD051852 | Pride

GLP-1 directed NMDA receptor antagonism for obesity treatment

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Temporal dynamics of the interstitial fluid proteome in human skeletal muscle following exhaustive exercise

Project description:The skeletal muscle interstitial space is the extracellular region around myofibres and mediates crosstalk between resident cell types. We applied a proteomic workflow to characterise the human skeletal muscle interstitial fluid proteome at rest and in response to exercise. Following exhaustive exercise, markers of skeletal muscle damage accumulate in the interstitial space followed in turn by the appearance of immune cell-derived proteins. Among the proteins upregulated after exercise, we identified cathelicidin-related antimicrobial peptide (CAMP) as a bioactive molecule regulating muscle fibre development. Treatment with the bioactive peptide derivative of CAMP (LL-37) resulted in the growth of larger C2C12 skeletal muscle myotubes. Phosphoproteomics revealed that LL-37 activated pathways central to muscle growth and proliferation, including PI3K, AKT, MAPKs, and mTOR. Our findings provide a proof-of-concept that the interstitial fluid proteome can be quantified via microdialysis sampling in vivo. Furthermore, these data highlight the importance of cellular communication in the adaptive response to exercise.

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