Effects of Growth Hormone and IGF-1 on Anabolic Signals and Stem Cell Recruitment in Human Skeletal Muscle

Study Overview
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Brief Summary
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12 adult hypopituitary patients with newly diagnosed Growth hormone (GH)-deficiency will be studied two times. The first examinations will be performed shortly after time of diagnose before initiation of exogenous GH treatment, where each subject will receive a single intravenous bolus of 0.5 mg GH. The examination day will be repeated after prolonged GH replacement therapy (>3 month after treatment initiation).

Detailed Description
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The overarching aim of this project is to investigate the mechanisms underlying loss of muscle mass in adults (sarcopenia) and the therapeutic potential of growth hormone (GH). The underlying hypothesis is that absence of GH and subsequent reduced insulin-like growth factor I (IGF-I) will impair normal proliferation of skeletal muscle stem cells and this is associated with metabolic dysfunction. GH is an important regulator of substrate metabolism and muscle mass. GH treatment reduces overall fat mass (FM) through lipolytic actions in adipose tissues and decreased adipose tissue triacylglycerol (TAG) synthesis. In skeletal muscle, exogenous GH administration production shifts substrate metabolism from glucose to lipid oxidation. In addition, GH mediates protein anabolic actions by production of IGF-I during sufficient nutrient supply and maintained insulin secretion. Circulating IGF-I is primarily produced in the liver, but animal studies suggest that locally produced autocrine and paracrine IGF-I is sufficient to maintain normal growth. GH deficiency (GHD) is a rare disorder characterized by the inadequate secretion of GH from the anterior pituitary gland and requires treatment with exogenous GH administration. Cell culture studies demonstrates that GH elicits insulin-like effects in cells deprived of GH. GH exerts its biological effects through binding to site 1 and 2 on the extracellular domain of a preformed GHR dimer. GHR activation initiates auto-phosphorylation of the receptor-associated Janus Kinase 2 (JAK2), which subsequently induces GHR cross-phosphorylation. The insulin-like effects are mediated by tyrosine phosphorylation of downstream targets including insulin receptor substrate-1 (IRS-1) and IRS-2. During physiological conditions, this signaling pathway is inhibited by the actions of a class of proteins known as suppressors of cytokine signaling (SOCSs). GHD in adults can be acquired as a result of trauma, infection, radiation therapy, or tumor growth within the brain. It is characterized by a number of variable symptoms including reduced energy levels, altered body composition and reduced muscle strength. Satellite cells (SCs), the skeletal muscle stem cells, are essential for muscle regeneration in genetic or autoimmune muscle diseases as well as after ischemic, chemical or mechanical trauma to the myofibers. Furthermore, SCs are the primary source to supply new myonuclei to growing myofibers during non-traumatic mechanical overload. In rats, GH-administration increases number of SCs in cross-sections of muscle fibres22, and fibre type composition in skeletal muscle is altered in animals with GHD. Together these findings indicate an importance of GH and IGF-I stimulation for muscle regeneration.

Official Title
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Effects of Growth Hormone and IGF-1 on Anabolic Signals and Stem Cell Recruitment in Human Skeletal Muscle

Conditions
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Growth Hormone Deficiency, Growth Hormone Treatment

Intervention / Treatment
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* Drug: Genotropin miniquick 0.5 mg, injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed adult onset growth hormone deficiency Exclusion Criteria: Documentation of Growth hormone deficiency for less than three months Pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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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Design Details

Primary Purpose: Basic Science
Intervention Model: Sequential Assignment
Interventional Model Description: All participants will be studies two times - one time before initiation of GH replacement therapy and one time following three months of GH replacement therapy. The two times are identical. The trial day includes infusion of tracers (glucose, tyrosine, phenylalanine, urea, palmitate), muscle biopsies, subcutaneous fat biopsies, an intravenous bolus of 0.5 mg GH, indirect calorimetry, plethysmography, blood samples, strength test, DXA scan and spectroscopy of liver and muscle.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: GHD<br>GHD patients will be studied two times - one time before initiation of GH replacement therapy and one time following three months of GH replacement therapy. The two trial days are identical | Drug: Genotropin miniquick 0.5 mg, injection<br>* GH will be given as an injection. Muscle biopsy will be obtained from m. vests laterals of the dominant leg. Fat biopsies will be obtained from subcutaneous abdominal fat. Tracers will be given as a bolus followed by continuous infusion for 6 hours. For palmitate tracer the infusion will be for only 1,5 hours followed by a one hour break and then another 1 hour infusion. Blood tests will be drawn from a venous catheter placed on the dorsal side of the hand.<br>* Other names: Tracers of metabolism, infusion;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phosphorylation of Akt in muscle biopsies | Muscle biopsies will be analysed for phosphorylation of Akt | Analyses will be performed through study completion, an expected average of 1.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Satellite cell count | The number of Satellite cells per muscle fiber will be analysed on muscle cross sections from muscle biopsies | Analyses will be performed through study completion, an expected average of 1.5 year | 
| Satellite cell proliferation and differentiation in cell culture | Analyses of satellite cells ability to proliferate and differentiate will be performed on cell culture following fluorescent activated cell sorting. Comparison will be between first and second visit. | Analyses will be performed through study completion, an expected average of 1.5 year | 
| Strength of muscle | assessed by isokinetic/dynamic measurements using a dynamometer | Analyses will be performed through study completion, an expected average of 1.5 year | 
| Muscle mass | Qualified by DXA scan | Analyses will be performed through study completion, an expected average of 1.5 year | 
| Glucose turnover rate | Evaluated through blood samples | Analyses will be performed through study completion, an expected average of 1.5 year | 
| Fatty acid turn over rate | evaluated through blood samples | Analyses will be performed through study completion, an expected average of 1.5 year | 
| Urea turnover rate | evaluated by blood samples and urin collection | Analyses will be performed through study completion, an expected average of 1.5 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Growth hormone, Satellite cells, Metabolism, insulin-like effects