Integrated proteomic and transcriptomic profiling identifies aberrant gene and protein expression in the sarcomere, mitochondrial complex I, and the extracellular matrix in Warmblood horses with myofibrillar myopathy

Abstract

Background Myofibrillar 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. Results We 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. Conclusions A 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.

A Combined Differential Proteome and Transcriptome Profiling of Fast- and Slow-Twitch Skeletal Muscle in Pigs

“…Additionally, the consistency between the genes and proteins expression was further validated through the quantification of DAPs using a real-time PCR method ( Figure S4 ). However, our results are not consistent with previous studies in human and mouse [ 32 , 33 ], in which, although the skeletal muscle tissues were used, an overall low correlation between mRNA and protein was observed. These differences may be influenced by species and physiological status.…”

Construction of Oxidative Stress-Related Genes Risk Model Predicts the Prognosis of Uterine Corpus Endometrial Cancer Patients

“…E2F1-deficient cells are hypersensitive to oxidative stress due to a defect in cell cycle arrest, and E2F1 sumoylation serves as a protective cellular mechanism during oxidative stress response [ 41 , 42 ]. CHAC1 is tightly associated with oxidative stress and apoptosis by degrading glutathione [ 43 ].…”

Absence of myofibrillar myopathy in Quarter Horses with a histopathological diagnosis of type 2 polysaccharide storage myopathy and lack of association with commercial genetic tests

“…A definitive cause for PSSM2 has yet to be identified and clinical signs vary among breeds, suggesting there may be several aetiologies grouped under the histopathological descriptor PSSM2 3 . Ultrastructural and immunohistochemical evaluation of skeletal muscle recently identified ectopic accumulation of the cytoskeletal protein desmin, myofibrillar disarray and Z disc disruption, and novel proteomic and transcriptomic profiles in a subset of Arabian and Warmblood PSSM2 horses 4‐7 . Based on the similarity of the histopathological findings in Arabian and Warmblood horses to a described myopathy in humans, the term myofibrillar myopathy (MFM) was applied to those horses in which abnormal desmin aggregates were identified 4,5,8‐10 .…”