Modelling energy metabolism dysregulations in neuromuscular diseases: A case study of calpainopathy

Biological modelling helps understanding complex processes, like energy metabolism, by predicting pathway compensations and equilibrium under given conditions. When deciphering metabolic adaptations, traditional experiments face challenges due to numerous enzymatic activities, needing modelling to anticipate pathway behaviours and orientate research. This paper aims to implement a constraint-based modelling method of muscular energy metabolism, adaptable to individual situations, energy demands, and complex disease-specific metabolic alterations like muscular dystrophy calpainopathy. Our calpainopathy-like model not only confirms the ATP production defect under increasing energy demands, but suggests compensatory mechanisms through anaerobic glycolysis. However, excessive glycolysis indicates a need to enhance mitochondrial respiration, preventing excess lactate production common in several diseases. Our model suggests that moderate-intensity physiotherapy, known to improve aerobic performance and anaerobic buffering, combined with increased carbohydrate and amino acid sources, could be a potent therapeutic approach for calpainopathy.