Common and Key Differential Pathogenic Pathways in Desminopathy and Titinopathy

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• Myofibrillar myopathy (MFM) comprises hereditary muscle disorders affecting striated muscles.
• Desminopathy and titinopathy are common MFM subtypes with distinct genetic origins.
• Understanding their pathomechanisms is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the distinct pathomechanisms of desminopathy and titinopathy using TMT-based proteomics.
• To identify common and differential protein expression patterns in these MFM subtypes.
• To uncover potential therapeutic targets for MFM.

Main Methods:

• Proteomic analysis using Tandem Mass Tag (TMT) labeling.
• High-resolution liquid chromatography-mass spectrometry (LC-MS) on muscle samples.
• Comparative analysis of differentially abundant proteins (DAPs) between patient groups and controls.

Main Results:

• Identified 436 DAPs in desminopathy and 269 in titinopathy versus controls.
• Desminopathy showed suppressed mitochondrial ATP production, muscle contraction, and cytoskeleton organization, with activated extracellular matrix (ECM) pathways.
• Titinopathy exhibited downregulated mitochondrial and ECM pathways, with activated gluconeogenesis. Hub genes in MFM subtypes were linked to glycolysis.

Conclusions:

• Cytoskeleton disorganization and mitochondrial dysfunction are common pathophysiological processes in MFM.
• Glycolysis and ECM alterations represent differential mechanisms between desminopathy and titinopathy.
• Findings provide a basis for targeted MFM therapies.