Enriched Pathways of Calcium Regulation, Cellular/Oxidative Stress, Inflammation, and Cell Proliferation Characterize Gluteal Muscle of Standardbred Horses between Episodes of Recurrent Exertional Rhabdomyolysis

Abstract

Certain Standardbred racehorses develop recurrent exertional rhabdomyolysis (RER-STD) for unknown reasons. We compared gluteal muscle histopathology and gene/protein expression between Standardbreds with a history of, but not currently experiencing rhabdomyolysis (N = 9), and race-trained controls (N = 7). Eight RER-STD had a few mature fibers with small internalized myonuclei, one out of nine had histologic evidence of regeneration and zero out of nine degeneration. However, RER-STD versus controls had 791/13,531 differentially expressed genes (DEG). The top three gene ontology (GO) enriched pathways for upregulated DEG (N = 433) were inflammation/immune response (62 GO terms), cell proliferation (31 GO terms), and hypoxia/oxidative stress (31 GO terms). Calcium ion regulation (39 GO terms), purine nucleotide metabolism (32 GO terms), and electron transport (29 GO terms) were the top three enriched GO pathways for down-regulated DEG (N = 305). DEG regulated RYR1 and sarcoplasmic reticulum calcium stores. Differentially expressed proteins (DEP ↑N = 50, ↓N = 12) involved the sarcomere (24% of DEP), electron transport (23%), metabolism (20%), inflammation (6%), cell/oxidative stress (7%), and other (17%). DEP included ↑superoxide dismutase, ↑catalase, and DEP/DEG included several cysteine-based antioxidants. In conclusion, gluteal muscle of RER-susceptible Standardbreds is characterized by perturbation of pathways for calcium regulation, cellular/oxidative stress, inflammation, and cellular regeneration weeks after an episode of rhabdomyolysis that could represent therapeutic targets.

New Pathophysiological Insights from Serum Proteome Profiling in Equine Atypical Myopathy

“…The surge of antioxidant enzymes within the proteomic profiles of the affected horses suggests an adaptive response to mitigate oxidative stress. This response aligns with analogous disturbances in pathways implicated in cellular and oxidative stress, as recently reported in cases of recurrent exertional rhabdomyolysis in horses . However, the sufficiency of endogenous antioxidant upregulation for complete quenching of ROS remains unanswered.…”

“…This response aligns with analogous disturbances in pathways implicated in cellular and oxidative stress, as recently reported in cases of recurrent exertional rhabdomyolysis in horses. 82 However, the sufficiency of endogenous antioxidant upregulation for complete quenching of ROS remains unanswered. As supplementation of vitamin complexes and antioxidants has been reported to help increase antioxidant defenses in horses, 83 our findings lend further credence to previous research highlighting the positive impact of this type of supplements to AM-affected horses.…”

Clinical Diagnosis of Rhabdomyolysis without Myoglobinuria or Electromyographic Abnormalities in a Dog

“…In the canine case we reported here, no clear etiology was identified. If RM episodes recur repeatedly after exertion, the term recurrent exertional RM is applicable (which has been extensively studied in horses) [1][2][3][4][5][6][7][8]25]. In the case reported here, no recurrences were noted over the 15-month follow-up period.…”

Identification of Differentially Expressed Genes after Endurance Runs in Karbadian Horses to Determine Candidates for Stress Indicators and Performance Capability

“…The strong involvement of the response to calcium ion is interesting and can be a reaction to oxidative stress within the blood during the endurance run. When examining Standardbred racehorses with recurrent exertional rhabdomyolysis, calcium ion regulation was significantly downregulated [37]. The activation of the Ca 2+ -sensitive K + channel increases the K + efflux and results in shrinkage of the cell and breakdown of phosphatidylserine asymmetry.…”

“…Further investigations, in which analysis of eQTLs [24], noncoding RNAs [25,26], or changes in the methylation pattern [27][28][29] are in the foreground, deal with possible causes of expression changes, try to uncover alternative splice variants [17,18], selective isoform expression, or protein-/expression-changing SNPs in the genes involved [30][31][32], or focus on the combination of several omics levels [33][34][35] to better understand the relationships between genotype and phenotype as well as the influence of the environment. The final result is to determine the genetic influences on diseases and, conversely, the genetic background for good health, welfare, and performance [36][37][38].…”