Pathophysiology of hypercortisolism-associated myopathy

• Applicants: Professor Dr. Martin Halle; Professor Dr. Martin Reincke; Professor Dr. Benedikt Schoser
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 440885333

Endogenous Cushing’s syndrome (CS) manifests itself as a multi-system disease in virtually all organ systems due to the universal expression of the glucocorticoid receptor. Late diagnosis of CS is associated with high morbidity and mortality. Our preliminary data among patients with CS suggests that impaired muscle function might be a major comorbidity associated with adverse long-term outcome and low health-related quality of life. Although mechanistic studies in humans are lacking, current evidence suggests that CS associated myopathy may result from multiple additive adverse factors. While the direct effects of glucocorticoids on the myocytes may be the most relevant factor, overall physical inactivity, malnutrition, gonadal steroid deficiency, psychiatric co-morbidity associated psychomotoric inactivity, and insulin resistance / hyperglycemia may contribute to myopathy as well. The overall aim of this application is the elucidation of the mechanisms underlying hypercortisolism-associated myopathy at the clinical and molecular level. Therefore, we will perform a two by two randomized-controlled clinical intervention study in 18 patients with active CS undergoing curative surgery and 18 age- and obesity-matched controls (both groups will be randomized to intervention versus control in 1:1 fashion). Patients and controls will be extensively phenotyped at baseline to identify clinical features predictive of CS myopathy (aim 1). Both groups will receive in a randomized fashion (1:1) a six months exercise training intervention or standard care. After 6 months, patients and controls will be re-evaluated to identify clinical and biochemical factors associated with myopathy improvement (aim 2). Muscle biopsies will be taken at baseline and after six months of physical training / control to study the molecular pathophysiology of CS associated myopathy (aim 3). Thereafter physical training will be introduced also to the control patients (month 7 to 12), and clinical evaluation will be repeated at the end of the study. We hypothesize that the training intervention during the randomized trial will improve muscle function and muscle morphology in CS in a significant fashion and unique for this population in comparison to an obese group without CS. In addition, changes in muscle structure, histopathology and transcriptomics will be instrumental for understanding the molecular mechanism leading to CS associated myopathy. Head-to-head comparison of baseline and follow-up muscle biopsy samples will allow direct quantitative studies on targeted and untargeted microRNA, mRNA and protein expression studies. In summary, we expect to clarify the pathways by which glucocorticoid excess exerts it unfavourable effects on muscle function in humans, but also the clinical and molecular mechanisms leading to muscle adaptation during physical training.

• DFG Programme: Research Grants