Dataset Information

Proteome and transcriptome profiling of equine myofibrillar myopathy identifies diminished peroxiredoxin 6 and enhanced cysteine metabolic pathways

ABSTRACT: Equine myofibrillar myopathy (MFM) causes exertional muscle pain and is characterized by myofibrillar disarray and ectopic protein aggregates of unknown origin. To investigate the pathophysiology of MFM, we compared the skeletal muscle proteome and 3 h post-exercise transcriptome of gluteal muscle in MFM and control Arabian horses using iTRAQ and RNA-sequencing analyses. Differential expression (DE) was evaluated using edgeR and pathway analysis using Cytoscape and Cluego. Proteome analysis revealed significantly lower antioxidant peroxiredoxin 6 content (PRDX6, ↓4.14 log2 fold change [FC]), sarcomere protein tropomyosin (TPM2, ↓3.24x) and higher fatty acid transport enzyme carnitine palmitoyl transferase (CPT1B, ↑3.49x) in MFM vs. control muscle at rest. Three hours after exercise, 191 genes were DE in MFM vs. control muscle with a remarkably focused > 1.5 log2FC in genes involved in sulfur compound/ cysteine metabolism such as cystathionine-beta-synthase [CBS, ↑4.51] and a cysteine and neutral amino acid membrane transporter [SLC7A10, ↑1.79]. In MFM vs. control at rest, 284 genes were DE with > 1.5 log2 FC in pathways for structure morphogenesis, fiber organization, tissue development and cell differentiation including> 2 log2 FC in alpha actin-cardiac [↑ ACTC1], cytoskeletal desmoplakin [↑ DSP], basement membrane usherin [↓ USH2A] and delta like non-canonical Notch ligand 1, [↓ DLK1]. In conclusion, myofibrillar disarray and protein aggregation in MFM horses was embodied by DE expression in pathways of structure/fiber organization and tissue regeneration. Reduced antioxidant capacity as a potential etiology for MFM was supported by diminished cysteine rich antioxidant peroxiredoxin 6 with compensatory increased cysteine synthesis following exercise.

OTHER RELATED OMICS DATASETS IN: GSE104388

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Equus Caballus (horse)

TISSUE(S): Gluteal Muscle

SUBMITTER: Sudeep Perumbakkam

LAB HEAD: Stephanie J Valberg

PROVIDER: PXD009362 | Pride | 2019-11-12

REPOSITORIES: Pride

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Proteome and transcriptome profiling of equine myofibrillar myopathy identifies diminished peroxiredoxin 6 and altered cysteine metabolic pathways.

Valberg Stephanie J SJ Perumbakkam Sudeep S McKenzie Erica C EC Finno Carrie J CJ

Physiological genomics 20181005 12

Equine myofibrillar myopathy (MFM) causes exertional muscle pain and is characterized by myofibrillar disarray and ectopic desmin aggregates of unknown origin. To investigate the pathophysiology of MFM, we compared resting and 3 h postexercise transcriptomes of gluteal muscle and the resting skeletal muscle proteome of MFM and control Arabian horses with RNA sequencing and isobaric tags for relative and absolute quantitation analyses. Three hours after exercise, 191 genes were identified as diff ...[more]

PMID: 30289745

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Project description:Pyruvate kinase M2 (PKM2), as the terminal and last rate-limiting enzyme of the glycolytic pathway, is an ideal enzyme for regulating metabolic phenotype. PKM2 tetramer activation has shown a protective role against diabetic kidney disease (DKD). However, the molecular mechanisms involved in diabetic tubular has not been investigated so far. In this study, we performed transcriptome gene expression profiling in human renal proximal tubular epithelial cell line (HK-2 cells) treated with high D-glucose (HG) for 7 days before the addition of 10-μM TEPP-46, an activator of PKM2 tetramerization, for a further 1 day in the presence of HG. Afterwards, we analyzed the differentially expressed (DE) genes and investigated gene relationships based on weighted gene co-expression network analysis (WGCNA). The results showed that 2,902 DE genes were identified (adjusted P-value ≤ 0.05), where 2,509 DE genes (86.46%) were co-expressed in the key module. Four extremely down-regulated DE genes (HSPA8, HSPA2, HSPA1B and ARRB1) and three extremely up-regulated DE genes (GADD45A, IGFBP3 and SIAH1) enriched in the down-regulated endocytosis (hsa04144) and up-regulated p53 signaling pathway (hsa04115), respectively, were validated by the qRT-PCR experiments. The qRT-PCR results showed that the relative expression levels of HSPA8 (adjusted P-value = 4.45×10-34 & log2(FC) = -1.12), HSPA2 (adjusted P-value = 6.09×10-14 & log2(FC) = -1.27), HSPA1B (adjusted P-value = 1.14×10-11 & log2(FC) = -1.02) and ARRB1 (adjusted P-value = 2.60×10-5 & log2(FC) = -1.13) were significantly different (P-value < 0.05) from case group to control group. Furthermore, the interactions and predicted microRNAs of the key genes (HSPA8, HSPA2, HSPA1B and ARRB1) were visualized in networks. This study identified the key candidate transcriptomic biomarkers and biological pathways in the hyperglycemic HK-2 cells responding to the PKM2 activator TEPP-46. These results will be valuable for further research on PKM2 in DKD.

Dataset Information

Proteome and transcriptome profiling of equine myofibrillar myopathy identifies diminished peroxiredoxin 6 and enhanced cysteine metabolic pathways

Publications

Proteome and transcriptome profiling of equine myofibrillar myopathy identifies diminished peroxiredoxin 6 and altered cysteine metabolic pathways.

Similar Datasets

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