Alterations of Muscle Secretome Associated With Muscle Atrophy Caused by Glucocorticoids

Cushing Syndrome Clinical Trial

— MYOSECRET  

Official title:

Alterations of Muscle Secretome Associated With Muscle Atrophy Caused by Glucocorticoids

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03229395
• Other study ID #: UCL-MYOSECRET 2014-1
• Status: Completed
• Phase: N/A
• First received: December 21, 2016
• Last updated: July 24, 2017
• Start date: January 2, 2014
• Est. completion date: July 18, 2017

Study information

• Verified date: December 2016
• Source: Cliniques universitaires Saint-Luc- Université Catholique de Louvain
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 35
• Est. completion date: July 18, 2017
• Est. primary completion date: July 13, 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Atrophy
• Cushing Syndrome
• Muscular Atrophy

Locations

Country	Name	City	State
Belgium	De Barsy Marie	Brussels

Sponsors (1)

Lead Sponsor	Collaborator
Cliniques universitaires Saint-Luc- Université Catholique de Louvain

Country where clinical trial is conducted

Belgium, 

References & Publications (15)

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Bortoluzzi S, Scannapieco P, Cestaro A, Danieli GA, Schiaffino S. Computational reconstruction of the human skeletal muscle secretome. Proteins. 2006 Mar 15;62(3):776-92. — View Citation

Braun TP, Grossberg AJ, Krasnow SM, Levasseur PR, Szumowski M, Zhu XX, Maxson JE, Knoll JG, Barnes AP, Marks DL. Cancer- and endotoxin-induced cachexia require intact glucocorticoid signaling in skeletal muscle. FASEB J. 2013 Sep;27(9):3572-82. doi: 10.10 — View Citation

Gueugneau M, Coudy-Gandilhon C, Théron L, Meunier B, Barboiron C, Combaret L, Taillandier D, Polge C, Attaix D, Picard B, Verney J, Roche F, Féasson L, Barthélémy JC, Béchet D. Skeletal muscle lipid content and oxidative activity in relation to muscle fib — View Citation

Henningsen J, Rigbolt KT, Blagoev B, Pedersen BK, Kratchmarova I. Dynamics of the skeletal muscle secretome during myoblast differentiation. Mol Cell Proteomics. 2010 Nov;9(11):2482-96. doi: 10.1074/mcp.M110.002113. Epub 2010 Jul 14. — View Citation

Hu Z, Wang H, Lee IH, Du J, Mitch WE. Endogenous glucocorticoids and impaired insulin signaling are both required to stimulate muscle wasting under pathophysiological conditions in mice. J Clin Invest. 2009 Oct;119(10):3059-69. doi: 10.1172/JCI38770. Epub — View Citation

Le Bihan MC, Bigot A, Jensen SS, Dennis JL, Rogowska-Wrzesinska A, Lainé J, Gache V, Furling D, Jensen ON, Voit T, Mouly V, Coulton GR, Butler-Browne G. In-depth analysis of the secretome identifies three major independent secretory pathways in differenti — View Citation

Mourtzakis M, Prado CM, Lieffers JR, Reiman T, McCargar LJ, Baracos VE. A practical and precise approach to quantification of body composition in cancer patients using computed tomography images acquired during routine care. Appl Physiol Nutr Metab. 2008 — View Citation

Neves M Jr, Barreto G, Boobis L, Harris R, Roschel H, Tricoli V, Ugrinowitsch C, Negrão C, Gualano B. Incidence of adverse events associated with percutaneous muscular biopsy among healthy and diseased subjects. Scand J Med Sci Sports. 2012 Apr;22(2):175- — View Citation

Pedersen BK. Muscle as a secretory organ. Compr Physiol. 2013 Jul;3(3):1337-62. doi: 10.1002/cphy.c120033. Review. — View Citation

Piccoli A. Patterns of bioelectrical impedance vector analysis: learning from electrocardiography and forgetting electric circuit models. Nutrition. 2002 Jun;18(6):520-1. — View Citation

Schakman O, Dehoux M, Bouchuari S, Delaere S, Lause P, Decroly N, Shoelson SE, Thissen JP. Role of IGF-I and the TNFa/NF-?B pathway in the induction of muscle atrogenes by acute inflammation. Am J Physiol Endocrinol Metab. 2012 Sep 15;303(6):E729-39. doi: — View Citation

Schakman O, Kalista S, Barbé C, Loumaye A, Thissen JP. Glucocorticoid-induced skeletal muscle atrophy. Int J Biochem Cell Biol. 2013 Oct;45(10):2163-72. doi: 10.1016/j.biocel.2013.05.036. Epub 2013 Jun 24. Review. — View Citation

Stastna M, Van Eyk JE. Secreted proteins as a fundamental source for biomarker discovery. Proteomics. 2012 Feb;12(4-5):722-35. doi: 10.1002/pmic.201100346. Epub 2012 Jan 19. Review. — View Citation

Webb SM, Badia X, Barahona MJ, Colao A, Strasburger CJ, Tabarin A, van Aken MO, Pivonello R, Stalla G, Lamberts SW, Glusman JE. Evaluation of health-related quality of life in patients with Cushing's syndrome with a new questionnaire. Eur J Endocrinol. 20 — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	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)
Primary	Muscle strenght measurement of Cushing's and control patients	Evalutation by dynamometer "Jamar type"	1 day (one assessment at diagnosis)
Primary	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)
Primary	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)