Clinical trial NCT03878992: Effects of Growth Hormone and IGF-1 on Anabolic Signals and Stem Cell Recruitment in Human Skeletal Muscle
Official title: Effects of Growth Hormone and IGF-1 on Anabolic Signals and Stem Cell Recruitment in Human Skeletal Muscle
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Growth Hormone Deficiency
Growth Hormone Treatment
Keywords: Growth hormone
Satellite cells
Metabolism
insulin-like effects
Lead sponsor: University of Aarhus
Sponsor class: OTHER
Collaborators: name: Aarhus University Hospital
First posted: 2019-03-18
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Intervention model: SEQUENTIAL
Intervention 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.
Primary purpose: BASIC_SCIENCE

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.

Eligibility criteria: Inclusion Criteria:

* Newly diagnosed adult onset growth hormone deficiency

Exclusion Criteria:

* Documentation of Growth hormone deficiency for less than three months
* Pregnancy

Primary outcomes:
measure: Phosphorylation of Akt in muscle biopsies
timeFrame: Analyses will be performed through study completion, an expected average of 1.5 years
Secondary outcomes:
measure: Satellite cell count
timeFrame: Analyses will be performed through study completion, an expected average of 1.5 year
measure: Satellite cell proliferation and differentiation in cell culture
timeFrame: Analyses will be performed through study completion, an expected average of 1.5 year
measure: Strength of muscle
timeFrame: Analyses will be performed through study completion, an expected average of 1.5 year
measure: Muscle mass
timeFrame: Analyses will be performed through study completion, an expected average of 1.5 year
measure: Glucose turnover rate
timeFrame: Analyses will be performed through study completion, an expected average of 1.5 year
measure: Fatty acid turn over rate
timeFrame: Analyses will be performed through study completion, an expected average of 1.5 year
measure: Urea turnover rate
timeFrame: Analyses will be performed through study completion, an expected average of 1.5 year
Other outcomes:
Locations:
city: Aarhus N
country: Denmark
facility: Department of Endcrinology
Study officials:
affiliation: Aarhus University Hospital
name: Jens Otto Jørgensen, Professor
role: STUDY_CHAIR
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