Abstract
BackgroundMyofibrillar myopathy in humans causes protein aggregation, degeneration, and weakness of skeletal muscle. In horses, myofibrillar myopathy is a late-onset disease of unknown origin characterized by poor performance, atrophy, myofibrillar disarray, and desmin aggregation in skeletal muscle. This study evaluated molecular and ultrastructural signatures of myofibrillar myopathy in Warmblood horses through gluteal muscle tandem-mass-tag quantitative proteomics (5 affected, 4 control), mRNA-sequencing (8 affected, 8 control), amalgamated gene ontology analyses, and immunofluorescent and electron microscopy.ResultsWe identified 93/1533 proteins and 47/27,690 genes that were significantly differentially expressed. The top significantly differentially expressed protein CSRP3 and three other differentially expressed proteins, including, PDLIM3, SYNPO2, and SYNPOL2, are integrally involved in Z-disc signaling, gene transcription and subsequently sarcomere integrity. Through immunofluorescent staining, both desmin aggregates and CSRP3 were localized to type 2A fibers. The highest differentially expressed gene CHAC1, whose protein product degrades glutathione, is associated with oxidative stress and apoptosis. Amalgamated transcriptomic and proteomic gene ontology analyses identified 3 enriched cellular locations; the sarcomere (Z-disc & I-band), mitochondrial complex I and the extracellular matrix which corresponded to ultrastructural Z-disc disruption and mitochondrial cristae alterations found with electron microscopy.ConclusionsA combined proteomic and transcriptomic analysis highlighted three enriched cellular locations that correspond with MFM ultrastructural pathology in Warmblood horses. Aberrant Z-disc mechano-signaling, impaired Z-disc stability, decreased mitochondrial complex I expression, and a pro-oxidative cellular environment are hypothesized to contribute to the development of myofibrillar myopathy in Warmblood horses. These molecular signatures may provide further insight into diagnostic biomarkers, treatments, and the underlying pathophysiology of MFM.
Highlights
Myofibrillar myopathy in humans causes protein aggregation, degeneration, and weakness of skeletal muscle
A combined proteomic and transcriptomic analysis highlighted three enriched cellular locations that correspond with Myofibrillar myopathy (MFM) ultrastructural pathology in Warmblood horses
Aberrant Z-disc mechano-signaling, impaired Z-disc stability, decreased mitochondrial complex I expression, and a pro-oxidative cellular environment are hypothesized to contribute to the development of myofibrillar myopathy in Warmblood horses
Summary
Myofibrillar myopathy in humans causes protein aggregation, degeneration, and weakness of skeletal muscle. Myofibrillar myopathy is a late-onset disease of unknown origin characterized by poor performance, atrophy, myofibrillar disarray, and desmin aggregation in skeletal muscle. The variety of genes causing desmin aggregate myopathies and the heterogeneous clinical signs that arise over a wide range of ages, suggest that the underlying basis for MFM is complex, influenced by both genetic and environmental factors [6, 7]. Paralleling MFM in humans, horses with MFM have myofilament disarray, Z-disc disruption, desmin aggregation, focal accumulation of granulofilamentous material and clusters of degenerate mitochondria in skeletal muscle [3, 8, 9, 11]. While an underlying genetic cause is still be possible, current findings suggest that MFM in WB is likely a complex disease with strong environmental influences. The etiopathology of MFM in WB could share similarities with the 50% of human MFM cases that have an unknown – potentially complex– etiology
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