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Background <p>Megaconial congenital muscular dystrophy (CMD) is an ultrarare autosomal recessive disorder characterized by phosphatidylcholine (PC) deficiency due to mutations in the choline kinase B (<i>CHKB)</i> gene. Although the genetic basis and morphological hallmarks of Megaconial CMD have been well characterized, the mechanisms by which lipid imbalance leads to global protein-level remodelling and muscle dysfunction remain poorly understood.</p> Methods <p>To address this gap, we performed label-free quantitative LC‒MS/MS proteomic profiling of primary skeletal myoblasts derived from a Megaconial CMD patient and healthy controls. The raw data were processed with Proteome Discoverer 2.2, and the candidate differentially abundant proteins (DAPs) were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses.</p> Results <p>Data quality assessment confirmed reliable clustering and clear separation between patient and control samples. A total of 218 candidate DAPs were identified, with the majority showing reduced abundance in patient-derived cells. GO and KEGG pathway enrichment analyses suggested enrichment of proteins associated with cytoskeletal organization, muscle contraction, actin–myosin filament sliding, and supramolecular fiber assembly. These findings suggest a potential association with early alterations in structural integrity and contractile machinery in myoblasts and indicate that PC deficiency may affect membrane organization and membrane–cytoskeleton interactions. Additional enriched pathways included protein homeostasis, endoplasmic reticulum processing, and stress response pathways, reflecting broad cellular perturbations. Notably, several cardiomyopathy-related pathways were also represented, likely reflecting shared sarcomeric and cytoskeletal components between skeletal and cardiac muscle.</p> Conclusion <p>To our knowledge, this study provides the first exploratory proteome-level characterization of Megaconial CMD skeletal myoblasts and identifies candidate protein alterations associated with muscle structural organization, cytoskeletal networks, and intracellular homeostasis, warranting further validation in independent biological samples.</p> Graphical Abstract <p></p>

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Exploratory proteomic analysis of Megaconial congenital muscular dystrophy skeletal myoblasts suggests cytoskeletal and contractile alterations

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月14日

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  • Evrim Aksu-Mengeş,
  • Gürler Akpınar,
  • Murat Kasap,
  • Burcu Balcı-Hayta

摘要

Background

Megaconial congenital muscular dystrophy (CMD) is an ultrarare autosomal recessive disorder characterized by phosphatidylcholine (PC) deficiency due to mutations in the choline kinase B (CHKB) gene. Although the genetic basis and morphological hallmarks of Megaconial CMD have been well characterized, the mechanisms by which lipid imbalance leads to global protein-level remodelling and muscle dysfunction remain poorly understood.

Methods

To address this gap, we performed label-free quantitative LC‒MS/MS proteomic profiling of primary skeletal myoblasts derived from a Megaconial CMD patient and healthy controls. The raw data were processed with Proteome Discoverer 2.2, and the candidate differentially abundant proteins (DAPs) were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses.

Results

Data quality assessment confirmed reliable clustering and clear separation between patient and control samples. A total of 218 candidate DAPs were identified, with the majority showing reduced abundance in patient-derived cells. GO and KEGG pathway enrichment analyses suggested enrichment of proteins associated with cytoskeletal organization, muscle contraction, actin–myosin filament sliding, and supramolecular fiber assembly. These findings suggest a potential association with early alterations in structural integrity and contractile machinery in myoblasts and indicate that PC deficiency may affect membrane organization and membrane–cytoskeleton interactions. Additional enriched pathways included protein homeostasis, endoplasmic reticulum processing, and stress response pathways, reflecting broad cellular perturbations. Notably, several cardiomyopathy-related pathways were also represented, likely reflecting shared sarcomeric and cytoskeletal components between skeletal and cardiac muscle.

Conclusion

To our knowledge, this study provides the first exploratory proteome-level characterization of Megaconial CMD skeletal myoblasts and identifies candidate protein alterations associated with muscle structural organization, cytoskeletal networks, and intracellular homeostasis, warranting further validation in independent biological samples.

Graphical Abstract