Decreased oxidative phosphorylation and PGAM deficiency in horses suffering from atypical myopathy associated with acquired MADD.

This study explores the link between Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) and the occurrence of atypical myopathy in horses, a frequently fatal illness. By examining the urine, plasma, and post-mortem muscle biopsies of affected horses, the authors found anomalies in creatine, purine and carbohydrate metabolism as well as oxidative phosphorylation which might be contributing factors to the onset of the disorder.

Methods and Findings

• The study focused on ten horses displaying signs of atypical myopathy, believed to be a consequence of MADD, a biochemical deficiency. The diagnostic materials used were pre-mortem plasma and urine samples as well as post-mortem muscle biopsies.
• The researchers observed a significant increase in creatine concentration, up to 17 times the normal level, in the urine of the patients. Similarly, uric acid concentration in these horses was four times more than that of the healthy control horses.
• The most severe glycogen depletion was noted in a subject showing the intense signs of myopathy, where glycolysis—a glucose breakdown process— was found to be higher than in other horses. This high metabolic activity may be the cause of the severe glycogen depletion.
• A patient horse showcased an unusually low Phosphoglycerate Mutase (PGAM) activity, less than 10% of the expected value. This enzyme plays a critical role in the glycolytic pathway, thus a deficiency can disrupt this metabolic process.
• Observations further revealed the decline in respiratory chain complex activity in patient horses, which was around 20-30% lower than that of healthy horses. Particularly, one subject exhibited a decrease of more than 60% in ATP-synthase activity, an enzyme crucial for energy production in cells.

Implications

• Common markers for muscle damage, or myopathy, that were monitored in this study include elevated levels of creatine kinase (CK) and lactic acid in plasma, and increased creatine and uric acid levels in urine.
• The researchers suggest that a broader examination of carbohydrate, lipid, and protein metabolism as well as oxidative phosphorylation should be conducted for a better understanding of the disease’s origin.
• This study furthers our understanding of atypical myopathy in horses and could potentially expand diagnostic approaches for equine myopathies by considering the anomalies in the metabolic pathways.