Altered Energetics of Exercise Explain Risk of Rhabdomyolysis in Very Long-Chain Acyl-CoA Dehydrogenase Deficiency

Area of Science:

• Exercise physiology
• Metabolic myopathies
• Biochemistry

Background:

• Rhabdomyolysis is a common complication in very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) and other metabolic myopathies.
• The underlying mechanisms linking VLCADD to exercise-induced muscle damage remain poorly understood.

Purpose of the Study:

• To investigate the basis of impaired muscle ATP homeostasis during exercise in VLCADD patients.
• To explore the relationship between exercise, energy metabolism, and rhabdomyolysis risk in VLCADD.

Main Methods:

• Prolonged bicycling exercise at a standardized moderate workload was performed by VLCADD patients and healthy controls.
• Muscle phosphocreatine (PCr) and inorganic phosphate (Pi) concentrations were measured using magnetic resonance spectroscopy.
• Plasma acetyl-carnitine levels were analyzed.
• Mathematical modeling of oxidative ATP metabolism was employed to analyze muscle fiber-type composition.

Main Results:

• VLCADD patients exhibited significantly larger changes in muscle PCr and Pi concentrations during exercise compared to healthy subjects.
• Plasma acetyl-carnitine levels showed a twofold lower change in VLCADD patients.
• Post-exercise recovery rates of PCr and Pi indicated normal mitochondrial ATP synthesis capacity in VLCADD muscle.
• Mathematical modeling suggested a slow-to-fast shift in quadriceps fiber-type composition in VLCADD patients.

Conclusions:

• Muscle ATP homeostasis is compromised during exercise in VLCADD, but not due to impaired mitochondrial function.
• Altered energy balance in VLCADD during exercise may stem from changes in muscle fiber-type composition.
• These findings provide novel insights into the pathogenesis of exercise-induced rhabdomyolysis in VLCADD.