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

September 25, 2019 updated by: University of Aarhus
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).

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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

Enrollment (Anticipated)

12

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Tine B Billeskov, PhD student
  • Phone Number: +4560169141
  • Email: tine@clin.au.dk

Study Contact Backup

  • Name: Jens Otto Jørgensen, Professor
  • Phone Number: +4578462025
  • Email: joj@clin.au.dk

Study Locations

  • Denmark
      • Aarhus N, Denmark, 8200
        • Recruiting
        • Department of Endcrinology
        • Contact:
          • Jens Otto L Jørgensen, MD, DMSc
          • Phone Number: +45 78462015
          • Email: joj@clin.au.dk
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 100 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Newly diagnosed adult onset growth hormone deficiency

Exclusion Criteria:

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: BASIC_SCIENCE
  • Interventional Model: SEQUENTIAL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
OTHER: GHD
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
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.
Other Names:
  • blood tests
  • Muscle biopsy
  • fat biopsy
  • pletysmography
  • Tracers of metabolism, infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Phosphorylation of Akt in muscle biopsies
Time Frame: Analyses will be performed through study completion, an expected average of 1.5 years
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
Time Frame: 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
Analyses will be performed through study completion, an expected average of 1.5 year
Satellite cell proliferation and differentiation in cell culture
Time Frame: 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.
Analyses will be performed through study completion, an expected average of 1.5 year
Strength of muscle
Time Frame: Analyses will be performed through study completion, an expected average of 1.5 year
assessed by isokinetic/dynamic measurements using a dynamometer
Analyses will be performed through study completion, an expected average of 1.5 year
Muscle mass
Time Frame: Analyses will be performed through study completion, an expected average of 1.5 year
Qualified by DXA scan
Analyses will be performed through study completion, an expected average of 1.5 year
Glucose turnover rate
Time Frame: Analyses will be performed through study completion, an expected average of 1.5 year
Evaluated through blood samples
Analyses will be performed through study completion, an expected average of 1.5 year
Fatty acid turn over rate
Time Frame: Analyses will be performed through study completion, an expected average of 1.5 year
evaluated through blood samples
Analyses will be performed through study completion, an expected average of 1.5 year
Urea turnover rate
Time Frame: Analyses will be performed through study completion, an expected average of 1.5 year
evaluated by blood samples and urin collection
Analyses will be performed through study completion, an expected average of 1.5 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Aarhus

Collaborators

Aarhus University Hospital

Investigators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

April 30, 2019

Primary Completion (ANTICIPATED)

March 1, 2021

Study Completion (ANTICIPATED)

December 31, 2021

Study Registration Dates

First Submitted

March 7, 2019

First Submitted That Met QC Criteria

March 13, 2019

First Posted (ACTUAL)

March 18, 2019

Study Record Updates

Last Update Posted (ACTUAL)

September 26, 2019

Last Update Submitted That Met QC Criteria

September 25, 2019

Last Verified

February 1, 2019

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • GHDSCs

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

There is no specific plan to share IPD at the moment. If this should be of interest it will only happen after approval from the local ethics committee

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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