Alterations of Muscle Secretome Associated With Muscle Atrophy Caused by Glucocorticoids

Study Overview
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Brief Summary
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Several studies have shown that lean mass, in particular muscle mass, is an excellent predictive survival factor in many diseases. A better knowledge of the mechanisms responsible for muscle atrophy and the identification of atrophic process markers are deeply needed for the development of new anti-atrophic therapies. Either as drugs used to treat several medical conditions or as endocrine hormones released in response to many stress situations (e.g., sepsis, cancer, insulinopenia…), glucocorticoids (GC) are recognized to play a major role in skeletal muscle atrophy. Indeed, the inhibition of GC action by a receptor antagonist (RU486) or by muscle-specific invalidation of the GC receptor inhibits the muscle atrophy in these stress situations. Therefore, all these data clearly indicate that GC play a major role in skeletal muscle atrophy observed in several conditions. Emerging evidence has revealed that the skeletal muscle has a secretory function. Human skeletal muscle secretome was first estimated at about 300 proteins by computational analysis and proteomic analysis have recently confirmed these results. Some of these secreted proteins, conceptualized as myokines, can act locally on muscle cells through autocrine/paracrine loops and on surrounding tissues such as muscle blood vessels or can be released into the blood stream to produce systemic effects. One prominent example is interleukin (IL)-6 which is released into circulation by contracting skeletal muscle and can regulate metabolic and inflammatory processes. As IL-6, several other potential myokines have been identified including IL-8, IL-15, insulin-growth factor I (IGF-I), follistatin-like 1 (FSTL1) or fibroblast-growth factor (FGF)-21. Moreover, secreted proteins may also reflected metabolic changes which take place in muscle cells. Indeed, myoblast differentiation is accompanied by dramatic changes in the secreted proteins profile as increased expression of Semaphorins, IGF-I, matrix metalloproteinase (MMP)-2 or Collagens. Thereby, the investigators hypothesized that skeletal muscle atrophy induced by GC is associated with specific alterations of the muscle secretome. The aim of this project is to identify the GC-induced changes in the secretome of human skeletal muscle cells in culture (in vitro approach) and to determine how these changes translate into the circulation of subjects exposed to high concentrations of GC (Cushing's syndrome) (in vivo approach). Characterization of these changes in human subjects should allow to better understand the cellular mechanisms involved in muscle atrophy and might lead to identify circulating biomarkers associated with skeletal muscle atrophy, as telopeptides are for bone tissue.

Official Title
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Alterations of Muscle Secretome Associated With Muscle Atrophy Caused by Glucocorticoids

Conditions
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Cushing Syndrome

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pituitary or adrenal endogenous Cushing's syndrome formally demonstrated by the standard endocrinological assessment New diagnosis or recurrence or persistent Cushing's syndrome after pituitary surgery Exclusion Criteria: Pseudo Cushing's syndrome Paraneoplasic Cushing's syndrome Cyclic Cushing's syndrome Adrenocortical carcinoma Pituitary irradiation during the last six months

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| patients with Cushing's syndrome<br>Patients were selected by the PI at the diagnosis. | |
| control patients<br>Selected patients are matched for age and sex. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of BMI in kg/m^2 | Measurement of weight in kilograms and height in meters to determine BMI as BMI=weight/height^2 | 1 day (one assessment at diagnosis) | 
| Evaluation of quality of life of Cushing's patients | The CushingQoL questionnaire was used to evaluate quality of life of Cushing's patients | 1 day (one assessment at diagnosis) | 
| Measure of body lean mass of Cushing's and control patients | Bioelectrical Impedance Vector Analysis (BIA) was used for evaluation of lean and fat mass. | 1 day (one assessment at diagnosis) | 
| Muscle strenght measurement of Cushing's and control patients | Evalutation by dynamometer Jamar type | 1 day (one assessment at diagnosis) | 
| Measurement of Mid-arm muscle circumference (MAMC, cm) | Measurement of triceps skinfold thickness (TSF, in cm), and midarm circumference (MAC, in cm) to determine the MAMC according to the following formula: MAMC= MAC - (Pi x TSF). MAMC is a bedside anthropometric measurement that estimates somatic protein reserve, an early indicator of nutritional depletion. | 1 day (one assessment at diagnosis) | 
| Evaluation of daily energy expenditure (DEE) of Cushing's and control patients | Evaluation of DEE by completing the QAPSE questionnaire. | 1 day (one assessment at diagnosis) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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skeletal muscle, muscle mass, glucocorticoids, biomarkers