Physical exercise in metabolic myopathies at risk of rhabdomyolysis: a feasible approach or an unavoidable hazard?

Metabolic myopathies are a diverse group of inherited genetic disorders that disrupt carbohydrate and fatty acid metabolism, leading to impaired production of adenosine triphosphate and consequently, compromised muscle function. In many of these conditions, regardless of the specific metabolic defect, physical exercise (PE) can induce rhabdomyolysis (RML), posing a significant health risk to patients. Except for Glycogen Storage Disease (GSD) Type V, for which specific PE guidelines are available, clinical management of these conditions typically advocates for substantial physical inactivity to prevent complications. However, while this strategy helps avoid RML and its dangerous consequences, such as acute kidney failure, it also exposes patients to several long-term risks, including a decline in physical efficiency, reduced autonomy, and the emergence of comorbidities. Therefore, it is crucial to identify disease-specific PE modalities that can be safely performed to improve clinical management and enhance patients' quality of life. The existing literature on this topic is generally limited, likely due to the rarity of these conditions. Nevertheless, a comprehensive analysis of the available evidence could provide a foundation for identifying feasible PE modalities and developing innovative strategies for adapting PE to different diseases. This review critically examines the current evidence on the effects and feasibility of PE in GSDs and fatty acid oxidation disorders, focusing on the distinction between aerobic and anaerobic exercise. Additionally, it explores the usefulness of supporting nutritional strategies while identifying literature gaps. Finally, based on the available data, novel theories for exercise adaptation are discussed, aiming for prospective validation in future studies.