McPhail Equine Performance Center, Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, Michigan.
Department of Population Sciences, University of Minnesota , St. Paul, Minnesota.
Physiol Genomics. 2018 Dec 1;50(12):1036-1050. doi: 10.1152/physiolgenomics.00044.2018. Epub 2018 Oct 5.
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.
马的肌原纤维肌病（MFM）导致运动性肌肉疼痛，其特征是肌原纤维排列紊乱和未知来源的结构蛋白-desmin 异位聚集。为了研究 MFM 的病理生理学，我们使用 RNA 测序和等重同位素标记相对和绝对定量分析（iTRAQ）比较了休息时和运动 3 小时后臀肌的转录组以及 MFM 和对照阿拉伯马的休息时骨骼肌蛋白质组。与对照肌肉相比，运动 3 小时后，MFM 肌肉中有 191 个基因差异表达（DE），涉及硫化合物/半胱氨酸代谢的基因如胱硫醚-β-合酶（CBS，↓4.51）、半胱氨酸和中性氨基酸膜转运体（SLC7A10，↓1.80 MFM）和阳离子转运体（SLC24A1，↓1.11 MFM）的基因变化倍数（FC）＞1 个对数。在休息时的 MFM 与对照相比，有 284 个基因差异表达（DE），其参与结构形态发生、纤维组织、组织发育和细胞分化的通路的 FC＞1 个对数，包括心脏α肌动蛋白（ACTC1，↑2.5 MFM）、细胞骨架桥粒斑蛋白（DSP，↑2.4 MFM）和基底膜 usherin（USH2A，↓2.9 MFM）。蛋白质组分析显示，休息时 MFM 肌肉中抗氧化剂过氧化物酶 6 含量显著降低（PRDX6，↓4.14 log FC MFM），脂肪酸转运酶肉碱棕榈酰转移酶（CPT1B，↑3.49 MFM）含量升高，肌球蛋白轻链 2（TPM2，↓3.24 MFM）含量降低。我们提出，在 MFM 马中，半胱氨酸代谢改变和含半胱氨酸的抗氧化剂缺乏，加上在有氧运动中氧化脂肪酸和产生 ROS 的能力增强，导致关键蛋白（如结构蛋白-desmin）的慢性氧化和聚集。
