Growth Hormone Deficiency Clinical Trial
Official title:
Effects of Growth Hormone and IGF-1 on Anabolic Signals and Stem Cell Recruitment in Human Skeletal Muscle
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).
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.
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