Effects of Growth Hormone and IGF-1 on Anabolic Signals and Stem Cell Recruitment in Human Skeletal Muscle
- Conditions
- Growth Hormone DeficiencyGrowth Hormone Treatment
- Interventions
- Registration Number
- NCT03878992
- Lead Sponsor
- University of Aarhus
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 12
- Newly diagnosed adult onset growth hormone deficiency
- Documentation of Growth hormone deficiency for less than three months
- Pregnancy
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description GHD Genotropin miniquick 0.5 mg, injection 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
- Primary Outcome Measures
Name Time Method Phosphorylation of Akt in muscle biopsies Analyses will be performed through study completion, an expected average of 1.5 years Muscle biopsies will be analysed for phosphorylation of Akt
- Secondary Outcome Measures
Name Time Method Fatty acid turn over rate Analyses will be performed through study completion, an expected average of 1.5 year evaluated through blood samples
Urea turnover rate Analyses will be performed through study completion, an expected average of 1.5 year evaluated by blood samples and urin collection
Satellite cell count Analyses will be performed through study completion, an expected average of 1.5 year The number of Satellite cells per muscle fiber will be analysed on muscle cross sections from muscle biopsies
Satellite cell proliferation and differentiation in cell culture Analyses will be performed through study completion, an expected average of 1.5 year 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.
Muscle mass Analyses will be performed through study completion, an expected average of 1.5 year Qualified by DXA scan
Glucose turnover rate Analyses will be performed through study completion, an expected average of 1.5 year Evaluated through blood samples
Strength of muscle Analyses will be performed through study completion, an expected average of 1.5 year assessed by isokinetic/dynamic measurements using a dynamometer
Trial Locations
- Locations (1)
Department of Endcrinology
🇩🇰Aarhus N, Denmark