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

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Brief Title

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

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.
    


Study Type

Interventional


Primary Outcome

Phosphorylation of Akt in muscle biopsies

Secondary Outcome

 Satellite cell count

Condition

Growth Hormone Deficiency

Intervention

Genotropin miniquick 0.5 mg, injection

Study Arms / Comparison Groups

 GHD
Description:  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

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

12

Start Date

April 30, 2019

Completion Date

December 31, 2021

Primary Completion Date

March 1, 2021

Eligibility Criteria

        Inclusion Criteria:

          -  Newly diagnosed adult onset growth hormone deficiency

        Exclusion Criteria:

          -  Documentation of Growth hormone deficiency for less than three months

          -  Pregnancy
      

Gender

All

Ages

18 Years - 100 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Jens Otto Jørgensen, Professor, +4560169141, [email protected]

Location Countries

Denmark

Location Countries

Denmark

Administrative Informations


NCT ID

NCT03878992

Organization ID

GHDSCs


Responsible Party

Sponsor

Study Sponsor

University of Aarhus

Collaborators

 Aarhus University Hospital

Study Sponsor

Jens Otto Jørgensen, Professor, Study Chair, Aarhus University Hospital


Verification Date

February 2019