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PloS one2021; 16(2); e0244556; doi: 10.1371/journal.pone.0244556

Pathways of calcium regulation, electron transport, and mitochondrial protein translation are molecular signatures of susceptibility to recurrent exertional rhabdomyolysis in Thoroughbred racehorses.

Abstract: Recurrent exertional rhabdomyolysis (RER) is a chronic muscle disorder of unknown etiology in racehorses. A potential role of intramuscular calcium (Ca2+) dysregulation in RER has led to the use of dantrolene to prevent episodes of rhabdomyolysis. We examined differentially expressed proteins (DEP) and gene transcripts (DEG) in gluteal muscle of Thoroughbred race-trained mares after exercise among three groups of 5 horses each; 1) horses susceptible to, but not currently experiencing rhabdomyolysis, 2) healthy horses with no history of RER (control), 3) RER-susceptible horses treated with dantrolene pre-exercise (RER-D). Tandem mass tag LC/MS/MS quantitative proteomics and RNA-seq analysis (FDR <0.05) was followed by gene ontology (GO) and semantic similarity of enrichment terms. Of the 375 proteins expressed, 125 were DEP in RER-susceptible versus control, with 52 ↑DEP mainly involving Ca2+ regulation (N = 11) (e.g. RYR1, calmodulin, calsequestrin, calpain), protein degradation (N = 6), antioxidants (N = 4), plasma membranes (N = 3), glyco(geno)lysis (N = 3) and 21 DEP being blood-borne. ↓DEP (N = 73) were largely mitochondrial (N = 45) impacting the electron transport system (28), enzymes (6), heat shock proteins (4), and contractile proteins (12) including Ca2+ binding proteins. There were 812 DEG in RER-susceptible versus control involving the electron transfer system, the mitochondrial transcription/translational response and notably the pro-apoptotic Ca2+-activated mitochondrial membrane transition pore (SLC25A27, BAX, ATP5 subunits). Upregulated mitochondrial DEG frequently had downregulation of their encoded DEP with semantic similarities highlighting signaling mechanisms regulating mitochondrial protein translation. RER-susceptible horses treated with dantrolene, which slows sarcoplasmic reticulum Ca2+ release, showed no DEG compared to control horses. We conclude that RER-susceptibility is associated with alterations in proteins, genes and pathways impacting myoplasmic Ca2+ regulation, the mitochondrion and protein degradation with opposing effects on mitochondrial transcriptional/translational responses and mitochondrial protein content. RER could potentially arise from excessive sarcoplasmic reticulum Ca2+ release and subsequent mitochondrial buffering of excessive myoplasmic Ca2+.
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Publication Date: 2021-02-10 PubMed ID: 33566847PubMed Central: PMC7875397DOI: 10.1371/journal.pone.0244556Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research presents a study on Thoroughbred racehorses, exploring the molecular mechanisms behind their susceptibility to recurrent exertional rhabdomyolysis (RER), a chronic muscle disorder. The study analysed the proteins and gene transcripts expressed in horse muscle post-exercise. The findings suggest that RER susceptibility relates to alterations in specific proteins, genes, and pathways connected to calcium regulation, protein degradation, and the function of mitochondria.

Analysis Protocol

  • The research focuses on the role of calcium (Ca2+) dysregulation in muscle cells, with the prior use of dantrolene – a muscle relaxant – to prevent rhabdomyolysis episodes influencing this focus.
  • Three groups of Thoroughbred race-trained mares were studied, five in each group. These included horses susceptible to rhabdomyolysis but not currently experiencing it, healthy horses with no RER history and RER-susceptible horses treated with dantrolene pre-exercise.
  • Using quantitative proteomics and RNA sequencing analysis, the study identified differentially expressed proteins (DEP) and gene transcripts (DEG) in the horses’ gluteal muscle after exercise.

Findings and Conclusions

  • The researchers identified 125 DEP in RER-susceptible versus control horses, notably those associated with calcium regulation and protein degradation. The altered expression of certain blood-borne proteins was also noted.
  • Decreased expression was found in mitochondrial proteins, affecting elements of the electron transport system and enzymes, among others. This process corresponds with the decrease in calcium binding proteins, which again points towards calcium dysregulation as a significant factor.
  • The team identified numerous DEG in RER-susceptible versus control horses, involving the electron transfer system, mitochondrial transcription/translational response and factors associated with the mitochondrial membrane transition pore activated by calcium.
  • Notably, the research suggests that horses treated with dantrolene, which slows the release of calcium from the sarcoplasmic reticulum, show no gene expression differences compared to control horses. This finding further cements the significance of calcium regulation in RER susceptibility.
  • Overall, the researchers have concluded that RER susceptibility in racehorses links to changes in proteins, genes, and pathways governing myoplasmic calcium regulation, mitochondrial function and protein degradation. The suggestion is the disorder could potentially arise from excessive calcium release from the sarcoplasmic reticulum and subsequent over-buffering of myoplasmic calcium by mitochondria.

Cite This Article

APA
Aldrich K, Velez-Irizarry D, Fenger C, Schott M, Valberg SJ. (2021). Pathways of calcium regulation, electron transport, and mitochondrial protein translation are molecular signatures of susceptibility to recurrent exertional rhabdomyolysis in Thoroughbred racehorses. PLoS One, 16(2), e0244556. https://doi.org/10.1371/journal.pone.0244556

Publication

PloS one
ISSN: 1932-6203
NlmUniqueID: 101285081
Country: United States
Language: English
Volume: 16
Issue: 2
Pages: e0244556

Researcher Affiliations

Aldrich, Kennedy
  • Mary Anne McPhail Equine Performance Center, Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, United States of America.
Velez-Irizarry, Deborah
  • Mary Anne McPhail Equine Performance Center, Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, United States of America.
Fenger, Clara
  • Equine Integrated Medicine, PLC, Lexington, KY, United States of America.
Schott, Melissa
  • Mary Anne McPhail Equine Performance Center, Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, United States of America.
Valberg, Stephanie J
  • Mary Anne McPhail Equine Performance Center, Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, United States of America.

MeSH Terms

  • Animals
  • Calcium / metabolism
  • Dantrolene / pharmacology
  • Disease Susceptibility / metabolism
  • Electron Transport / physiology
  • Female
  • Genetic Predisposition to Disease / genetics
  • Horse Diseases / metabolism
  • Horses / metabolism
  • Mitochondria / metabolism
  • Mitochondrial Proteins / metabolism
  • Muscle, Skeletal / metabolism
  • Physical Exertion
  • Rhabdomyolysis / metabolism
  • Rhabdomyolysis / physiopathology
  • Tandem Mass Spectrometry / methods

Grant Funding

  • T32 OD011167 / NIH HHS

Conflict of Interest Statement

One of the authors (CF) is a practicing veterinarian and owner of the business Equine Integrated Medicine PLC. There are no other relevant declarations relating to employment, consultancy, patents, products in development, or marketed products. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

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