Steroid Myopathy: Understanding the pathogenesis

Muscle plasticity is a key element in human health and disease. Exercise is an important element that leads to many positive adaptations, which improve survival and quality of life. Conversely, muscle atrophy is a condition found in many chronic diseases. Atrophy is the oucome of an imbalance between the processes that lead to protein synthesis (MPS) and the processes that lead to muscle protein breakdown (MPB) resulting in net muscle mass loss. Chronic administration of glucocorticoids causes steroid myopathy characterized by muscle weakness, fatigue and atrophy. The primary pathogenetic phenomenon causing such condition is still unknown. The present study aims to identify the molecular phenomena involved in triggering the myopathic process. To achieve such goal, the adapations of intracellular signalling pathways which have been previously shown to be potentially involved in steroid myopathy were studied. A single dose of desametasone (DEX) was administered intravenously to healthy subjects. Muscle biopsies were taken from vastus lateralis muscle 1h, 4h and 8h after DEX injection. Western blot and real time PCR were used to assess the adaptations of markers related to the ubiquitine-protesome degradation pathway (UPS), protein synthesis, autophagy, muscle metabolism, redox status and mitochondrial remodelling. Results suggest that DEX induced increased gene expression of Atrogin1, mitochondrial dysfunction and impairment of oxidative metabolism. The latter phenomenon would cause redox imbalance. Redox imbalance could further stimulate muscle MPB. This vicious loop results in an increased activation of the autophagy pathway. The activation of the autophagy process together with the activation of the pathway of protein degradation would finally lead to muscle atrophy. The ability by two-week intake of a mixture of branched chain amino to counteract the effects of DEX on intracellular pathways have been also tested. Preliminary data are reported.