Pathways of calcium regulation, electron transport, and mitochondrial protein translation are molecular signatures of susceptibility to recurrent exertional rhabdomyolysis in Thoroughbred racehorses.
Authors: Aldrich Kennedy, Velez-Irizarry Deborah, Fenger Clara, Schott Melissa, Valberg Stephanie J
Journal: PloS one
Summary
# Editorial Summary: Molecular Mechanisms of Recurrent Exertional Rhabdomyolysis in Thoroughbreds Recurrent exertional rhabdomyolysis (RER) remains a poorly understood chronic muscle condition affecting performance in Thoroughbred racehorses, with calcium dysregulation emerging as a potential culprit — a theory that has already influenced clinical practice through dantrolene use. Kennedy and colleagues conducted a sophisticated molecular analysis comparing gluteal muscle tissue from RER-susceptible mares, healthy controls, and dantrolene-treated RER-susceptible horses following exercise, utilising tandem mass tag proteomics and RNA sequencing to identify 125 differentially expressed proteins and 812 differentially expressed genes. The findings revealed a striking pattern: whilst calcium-regulatory proteins (including ryanodine receptor, calmodulin and calsequestrin) were substantially upregulated in susceptible horses, 73 proteins were downregulated—predominantly mitochondrial proteins critical for electron transport and ATP synthesis—despite the concurrent upregulation of genes encoding these same proteins, suggesting a translational block. Most compellingly, dantrolene-treated horses showed normalised gene expression patterns indistinguishable from healthy controls, supporting the hypothesis that RER arises from excessive sarcoplasmic reticulum calcium release that overwhelms the mitochondrial calcium buffering capacity. These molecular signatures have immediate clinical relevance: they validate dantrolene's preventative mechanism and suggest future therapeutic targets might focus on enhancing mitochondrial function or stabilising calcium handling, whilst also identifying potential genetic markers to identify susceptible horses before clinical episodes occur.
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Practical Takeaways
- •Dantrolene pre-exercise treatment appears effective at preventing RER episodes by blocking excessive calcium release from muscle storage sites; consider recommending this pharmaceutical intervention for RER-susceptible racehorses.
- •RER is fundamentally a calcium regulation disorder affecting mitochondrial function rather than a simple muscle fatigue issue; this molecular understanding supports early intervention in susceptible horses before clinical episodes occur.
- •Genetic/molecular screening of racing prospects for RER-susceptibility biomarkers (calcium regulation and mitochondrial protein expression patterns) could enable preventive management strategies before rhabdomyolysis occurs.
Key Findings
- •RER-susceptible horses showed 125 differentially expressed proteins compared to controls, with 52 upregulated proteins primarily involved in calcium regulation (RYR1, calmodulin, calsequestrin, calpain) and 73 downregulated proteins mostly mitochondrial in origin affecting electron transport systems.
- •812 differentially expressed genes in RER-susceptible horses implicated pathways for electron transfer, mitochondrial transcription/translation, and pro-apoptotic calcium-activated membrane transition pore mechanisms.
- •Dantrolene treatment, which inhibits sarcoplasmic reticulum calcium release, eliminated all differentially expressed genes in treated RER-susceptible horses compared to controls, supporting excessive calcium release as the primary mechanism.
- •RER pathophysiology involves dysregulated myoplasmic calcium regulation leading to mitochondrial calcium buffering, electron transport impairment, and disrupted mitochondrial protein translation.