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

• Published in: Physiological genomics Vol. 50; no. 12; pp. 1036 - 1050
• Main Authors: Valberg, Stephanie J, Perumbakkam, Sudeep, McKenzie, Erica C, Finno, Carrie J
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.12.2018
• Series: Omic Approaches to Understanding Muscle Biology
• Subjects: Actin; Aerobic capacity; Amino acids; Animals; Antioxidants; Antioxidants - metabolism; Basement Membrane - metabolism; Carnitine; Cell Differentiation - physiology; Cysteine; Cysteine - metabolism; Cytoskeleton; Desmin; Exercise; Fatty acids; Fatty Acids - metabolism; Female; Gene expression; Gene Expression Profiling - methods; Horses; Male; Metabolic Networks and Pathways - physiology; Metabolic pathways; Metabolism; Morphogenesis; Muscle Proteins - metabolism; Muscle, Skeletal - metabolism; Myopathies, Structural, Congenital - metabolism; Myopathy; Oxidation; Pain; Peroxiredoxin; Peroxiredoxin VI - metabolism; Physical Conditioning, Animal - physiology; Proteome - metabolism; Proteomes; Quantitation; Reactive oxygen species; Reactive Oxygen Species - metabolism; Ribonucleic acid; RNA; Skeletal muscle; Sulfur compounds; Tropomyosin; USH2A protein; horse; antioxidant; RNA-Seq; myopathy; transcriptome; proteome
• ISSN: 1094-8341; 1531-2267
• DOI: 10.1152/physiolgenomics.00044.2018

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 differentially expressed (DE) in MFM vs. control muscle with >1 log fold change (FC) in genes involved in sulfur compound/cysteine metabolism such as cystathionine-beta-synthase ( CBS, ↓4.51), a cysteine and neutral amino acid membrane transporter ( SLC7A10, ↓1.80 MFM), and a cationic transporter (SLC24A1, ↓1.11 MFM). In MFM vs. control at rest, 284 genes were DE with >1 log FC in pathways for structure morphogenesis, fiber organization, tissue development, and cell differentiation including > 1 log FC in cardiac alpha actin ( ACTC1 ↑2.5 MFM), cytoskeletal desmoplakin ( DSP ↑2.4 MFM), and basement membrane usherin ( USH2A ↓2.9 MFM). Proteome analysis revealed significantly lower antioxidant peroxiredoxin 6 content (PRDX6, ↓4.14 log FC MFM), higher fatty acid transport enzyme carnitine palmitoyl transferase (CPT1B, ↑3.49 MFM), and lower sarcomere protein tropomyosin (TPM2, ↓3.24 MFM) in MFM vs. control muscle at rest. We propose that in MFM horses, altered cysteine metabolism and a deficiency of cysteine-containing antioxidants combined with a high capacity to oxidize fatty acids and generate ROS during aerobic exercise causes chronic oxidation and aggregation of key proteins such as desmin.