Thoroughbred horses susceptible to Recurrent Exertional Rhabdomyolysis have elevated skeletal muscle mitochondrial capacities.

Overview

• This study investigated the skeletal muscle mitochondrial function in Thoroughbred horses susceptible to Recurrent Exertional Rhabdomyolysis (RER), a condition that causes muscle stiffness and damage during exercise.
• Contrary to expectations, RER-susceptible horses showed higher mitochondrial capacity in their muscles compared to healthy controls, suggesting altered calcium handling affects mitochondrial function.

Background

• Recurrent Exertional Rhabdomyolysis (RER): A muscle disease common in athletic horses characterized by episodes of muscle stiffness, pain, and damage that can interrupt training and competition.
• Cause of RER: Linked to abnormal regulation of intracellular calcium (Ca). Normally, Ca is released from the sarcoplasmic reticulum to trigger muscle contraction.
• Calcium and mitochondria: Calcium can enter mitochondria and influence their energy production capacity, so disturbances in calcium regulation may affect mitochondrial function.
• Mitochondrial protein expression in RER: Previous studies showed a paradoxical pattern where mitochondrial proteins are reduced but mitochondrial genes are upregulated, suggesting complex regulation of mitochondria in RER horses.

Research Objective

• To test whether Thoroughbred horses with a history of RER episodes have impaired skeletal muscle mitochondrial capacities compared to control racehorses without such history.
• Specifically, they assessed mitochondrial oxidative phosphorylation and electron transfer capacity in muscle biopsies using high-resolution respirometry.

Methods

• Subjects: 14 female Thoroughbred horses at race fitness level, divided into two groups:
  • RER-susceptible group (n = 8) with at least 2 past ER episodes, average age ~3.1 years
  • Control group (n = 6) with no history of ER, average age ~3.5 years
• Muscle sampling: Biopsies taken from the gluteus medius muscle, a major locomotor muscle.
• Measurements:
  • Oxidative phosphorylation capacity (OXPHOS, denoted as P)
  • Electron transfer system (ETS) capacity (denoted as E)
  • Substrate-specific respiration rates linked to NADH (complex I), succinate (complex II), and maximal capacities
  • Data reported as integrative (per mg of tissue) and intrinsic (normalized to citrate synthase activity, a marker of mitochondrial content) respiratory capacities

Key Findings

• Contrary to the initial hypothesis, RER-susceptible horses tended to have:
  • Higher integrative NADH-linked, maximal oxidative phosphorylation (P), and electron transfer (E) capacities (p ≤ 0.1, indicating a trend)
  • Higher intrinsic maximal OXPHOS (P) and ETS (E) capacities normalized to mitochondrial content (p ≤ 0.1)
  • Statistically significant increases in intrinsic succinate-linked OXPHOS and ETS capacities (p ≤ 0.03) compared to controls
• These results indicate that the mitochondria in skeletal muscle of RER-susceptible horses have elevated functional capacities rather than impairment.
• This may reflect compensatory changes in response to abnormal intracellular calcium handling that characterizes RER.

Implications

• The elevated mitochondrial capacity could be a consequence of altered calcium signaling affecting mitochondrial metabolism.
• The clinical impact of heightened mitochondrial function in RER is not yet clear—whether it contributes to disease severity, protection, or is a secondary adaptation remains to be determined.
• Understanding these mitochondrial changes might lead to new therapies targeting mitochondrial function to better manage or treat RER in horses.
• Future research directions could include:
  • Examining mitochondrial calcium handling and signaling pathways in RER-susceptible muscle
  • Investigating whether mitochondrial-targeted drugs or nutritional supplements can improve clinical outcomes
  • Longitudinal studies to see how mitochondrial function relates to episode frequency and severity

Summary

• In summary, Thoroughbred horses prone to recurrent muscle disease actually show increased mitochondrial respiratory capacities in their skeletal muscle.
• This unexpected result highlights the complex interplay between calcium regulation and mitochondrial function in muscle health and disease.
• The findings provide a foundation for further work to explore mitochondrial-focused interventions to benefit horses affected by RER.