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Does Human Skeletal Muscle Possess an Epigenetic Memory of Testosterone?

Primary Purpose

Healthy Aging, Age-Related Sarcopenia, Testosterone Deficiency

Status
Not yet recruiting
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Saline
Testosterone Undecanoate
Sponsored by
Norwegian School of Sport Sciences
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Healthy Aging focused on measuring Healthy aging, Preventing Age-related Sarcopenia, Overcoming Anabolic Resistance, Anti-Doping

Eligibility Criteria

55 Years - 70 Years (Adult, Older Adult)MaleAccepts Healthy Volunteers

Inclusion Criteria: Sedentary males 55-70 years old Serum testosterone levels >8 nmol/L measured in the morning Without any known illness, disease or other conditions Undergone screening through medical questionnaire, physical examination, routine blood tests and urine sample Written informed consent received Exclusion Criteria: Current or previous participation in a formal exercise regime A BMI < 18 or > 30 kg·m2 Active cardiovascular disease: uncontrolled hypertension (BP > 160/100 mmHg), angina, heart failure (class III/IV), arrhythmia, right to left cardiac shunt, recent cardiac event Family history of early (<55y) death from cardiovascular disease Haematocrit >50% Malignancy Prostate-specific antigen (PSA) >4 ng/mL Lower urinary tract symptoms Taking beta-adrenergic blocking agents, statins, non-steroidal anti-inflammatory drugs Cerebrovascular disease: previous stroke, aneurysm (large vessel or intracranial), epilepsy Respiratory diseases including: pulmonary hypertension, chronic obstructive pulmanary disease (COPD), asthma, sleep apnoea Metabolic disease: hyper and hypo parathyroidism, untreated hyper and hypothyroidism, Cushing's disease, type 1 or 2 diabetes Active inflammatory bowel or renal disease Current or previous steroid treatment or hormone replacement therapy Clotting dysfunction Musculoskeletal or neurological disorders Alcohol or drug abuse

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm 3

    Arm 4

    Arm Type

    Placebo Comparator

    Experimental

    Placebo Comparator

    Experimental

    Arm Label

    Placebo

    Testosterone Undecanoate

    Resistance exercise training + Placebo

    Resistance exercise training + Testosterone Undecanoate

    Arm Description

    The placebo group will complete 10-week treatment period where they continue with their regular habitual daily physical activity and receive two placebo (saline) injections (at baseline and week 3). They will then undergo a 12-week period with no treatment and no training, where they just do their regular habitual daily physical activity. Before they undertake a period of structured, progressive resistance training for 10-weeks. Questionnaires, physiological and psychological measures, skeletal muscle biopsies and blood samples will be taken at time points of: Baseline (week 0) Treatment period (week 10) Detraining and placebo abstinence (week 22) Retraining (week 32)

    The testosterone group will complete 10-week treatment period where they continue with their regular habitual daily physical activity and receive two testosterone undecanoate (Nebido) injections (1000 mg/4 ml at baseline and 500 mg/2 ml week 3). They will then undergo a 12-week period with no treatment and no training, where they just do their regular habitual daily physical activity. Before they undertake a period of structured, progressive resistance training for 10-weeks. Questionnaires, physiological and psychological measures, skeletal muscle biopsies and blood samples will be taken at time points of: Baseline (week 0) Treatment period (week 10) Detraining and testosterone abstinence (week 22) Retraining (week 32)

    The resistance exercise training + placebo group will complete 10-week treatment period where they undergo a period of structured, progressive resistance training and receive two placebo (saline) injections (at baseline and week 3). They will then undergo a 12-week period with no treatment and no training, where they return to their regular habitual daily physical activity. Before they undertake a second period of structured, progressive resistance training for 10-weeks. Questionnaires, physiological and psychological measures, skeletal muscle biopsies and blood samples will be taken at time points of: Baseline (week 0) Treatment period (week 10) Detraining and placebo abstinence (week 22) Retraining (week 32)

    The resistance exercise training + testosterone group will complete 10-week treatment period where they undergo a period of structured, progressive resistance training and receive two testosterone undecanoate (Nebido) injections (1000 mg/4 ml at baseline and 500 mg/2 ml week 3). They will then undergo a 12-week period with no treatment and no training, where they return to their regular habitual daily physical activity. Before they undertake a second period of structured, progressive resistance training for 10-weeks. Questionnaires, physiological and psychological measures, skeletal muscle biopsies and blood samples will be taken at time points of: Baseline (week 0) Treatment period (week 10) Detraining and testosterone abstinence (week 22) Retraining (week 32)

    Outcomes

    Primary Outcome Measures

    Fat-free mass
    Change and differences in fat-free mass (g) measured by dual x-ray absorptiometry (DEXA).
    Skeletal muscle size and cross-sectional area (CSA)
    Change and differences in skeletal muscle size and CSA measured by ultrasound
    Skeletal muscle fibre CSA
    Change and differences in skeletal muscle fibre CSA measure determined by immunohistochemistry

    Secondary Outcome Measures

    DNA methylation in skeletal muscle and blood
    Methylation measured in difference/fold change values relative to appropriate controls.
    Gene expression in skeletal muscle and blood
    Gene expression measured in difference/fold change values relative to appropriate controls.
    Myonuclei
    Change and differences in number of myonuclei determined by immunohistochemistry
    Satellite cells
    Change and differences in number of satellite cells determined by immunohistochemistry
    Isometric muscle strength
    Change and differences in peak muscle strength (N) using isokinetic dynamometry
    Dynamic muscle strength
    Change and differences in 1-repetition maximum
    Muscle force-velocity profiling
    Change and differences in force (N) and velocity (m/s) derived from a 10-repetition FV-test

    Full Information

    First Posted
    June 16, 2023
    Last Updated
    July 19, 2023
    Sponsor
    Norwegian School of Sport Sciences
    Collaborators
    Oslo University Hospital
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05964920
    Brief Title
    Does Human Skeletal Muscle Possess an Epigenetic Memory of Testosterone?
    Official Title
    Does Human Skeletal Muscle Possess an Epigenetic Memory of Testosterone?
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    July 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    August 1, 2023 (Anticipated)
    Primary Completion Date
    June 30, 2024 (Anticipated)
    Study Completion Date
    October 30, 2024 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    Norwegian School of Sport Sciences
    Collaborators
    Oslo University Hospital

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Product Manufactured in and Exported from the U.S.
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    This project's primary aim of this double-blinded, randomised, placebo-controlled trial is to investigate whether short-term testosterone administration +/- resistance exercise training induces a muscle memory response that can lead to longer-lasting benefits in aged human skeletal muscle. The investigators will provide older men with the anabolic hormone, testosterone or placebo, with or without resistance training, followed by a period of testosterone abstinence and detraining, followed by a subsequent repeated period of resistance training (retraining). This will help determine if earlier encounters with short-term testosterone administration can be "remembered" and if adaptation to later retraining can be enhanced as a consequence of encountering testosterone earlier.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Healthy Aging, Age-Related Sarcopenia, Testosterone Deficiency
    Keywords
    Healthy aging, Preventing Age-related Sarcopenia, Overcoming Anabolic Resistance, Anti-Doping

    7. Study Design

    Primary Purpose
    Basic Science
    Study Phase
    Phase 2, Phase 3
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantInvestigatorOutcomes Assessor
    Allocation
    Randomized
    Enrollment
    40 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Placebo
    Arm Type
    Placebo Comparator
    Arm Description
    The placebo group will complete 10-week treatment period where they continue with their regular habitual daily physical activity and receive two placebo (saline) injections (at baseline and week 3). They will then undergo a 12-week period with no treatment and no training, where they just do their regular habitual daily physical activity. Before they undertake a period of structured, progressive resistance training for 10-weeks. Questionnaires, physiological and psychological measures, skeletal muscle biopsies and blood samples will be taken at time points of: Baseline (week 0) Treatment period (week 10) Detraining and placebo abstinence (week 22) Retraining (week 32)
    Arm Title
    Testosterone Undecanoate
    Arm Type
    Experimental
    Arm Description
    The testosterone group will complete 10-week treatment period where they continue with their regular habitual daily physical activity and receive two testosterone undecanoate (Nebido) injections (1000 mg/4 ml at baseline and 500 mg/2 ml week 3). They will then undergo a 12-week period with no treatment and no training, where they just do their regular habitual daily physical activity. Before they undertake a period of structured, progressive resistance training for 10-weeks. Questionnaires, physiological and psychological measures, skeletal muscle biopsies and blood samples will be taken at time points of: Baseline (week 0) Treatment period (week 10) Detraining and testosterone abstinence (week 22) Retraining (week 32)
    Arm Title
    Resistance exercise training + Placebo
    Arm Type
    Placebo Comparator
    Arm Description
    The resistance exercise training + placebo group will complete 10-week treatment period where they undergo a period of structured, progressive resistance training and receive two placebo (saline) injections (at baseline and week 3). They will then undergo a 12-week period with no treatment and no training, where they return to their regular habitual daily physical activity. Before they undertake a second period of structured, progressive resistance training for 10-weeks. Questionnaires, physiological and psychological measures, skeletal muscle biopsies and blood samples will be taken at time points of: Baseline (week 0) Treatment period (week 10) Detraining and placebo abstinence (week 22) Retraining (week 32)
    Arm Title
    Resistance exercise training + Testosterone Undecanoate
    Arm Type
    Experimental
    Arm Description
    The resistance exercise training + testosterone group will complete 10-week treatment period where they undergo a period of structured, progressive resistance training and receive two testosterone undecanoate (Nebido) injections (1000 mg/4 ml at baseline and 500 mg/2 ml week 3). They will then undergo a 12-week period with no treatment and no training, where they return to their regular habitual daily physical activity. Before they undertake a second period of structured, progressive resistance training for 10-weeks. Questionnaires, physiological and psychological measures, skeletal muscle biopsies and blood samples will be taken at time points of: Baseline (week 0) Treatment period (week 10) Detraining and testosterone abstinence (week 22) Retraining (week 32)
    Intervention Type
    Drug
    Intervention Name(s)
    Saline
    Other Intervention Name(s)
    Placebo
    Intervention Description
    Two placebo injections one at baseline and one week 3.
    Intervention Type
    Drug
    Intervention Name(s)
    Testosterone Undecanoate
    Other Intervention Name(s)
    Nebido, Grünenthal (Grünenthal Norway AS)
    Intervention Description
    Two testosterone undecanoate injections, 1000 mg/4 ml at baseline, 500 mg/2 ml at week 3.
    Primary Outcome Measure Information:
    Title
    Fat-free mass
    Description
    Change and differences in fat-free mass (g) measured by dual x-ray absorptiometry (DEXA).
    Time Frame
    Baseline and weeks 10, 22, 32
    Title
    Skeletal muscle size and cross-sectional area (CSA)
    Description
    Change and differences in skeletal muscle size and CSA measured by ultrasound
    Time Frame
    Baseline and week 5,10, 16, 22, 27, 32
    Title
    Skeletal muscle fibre CSA
    Description
    Change and differences in skeletal muscle fibre CSA measure determined by immunohistochemistry
    Time Frame
    Baseline and weeks 10, 22, 32
    Secondary Outcome Measure Information:
    Title
    DNA methylation in skeletal muscle and blood
    Description
    Methylation measured in difference/fold change values relative to appropriate controls.
    Time Frame
    Baseline and weeks 10, 22, 32
    Title
    Gene expression in skeletal muscle and blood
    Description
    Gene expression measured in difference/fold change values relative to appropriate controls.
    Time Frame
    Baseline and weeks 10, 22, 32
    Title
    Myonuclei
    Description
    Change and differences in number of myonuclei determined by immunohistochemistry
    Time Frame
    Baseline and weeks 10, 22, 32
    Title
    Satellite cells
    Description
    Change and differences in number of satellite cells determined by immunohistochemistry
    Time Frame
    Baseline and weeks 10, 22, 32
    Title
    Isometric muscle strength
    Description
    Change and differences in peak muscle strength (N) using isokinetic dynamometry
    Time Frame
    Baseline and weeks 5, 10, 16, 22, 27, 32
    Title
    Dynamic muscle strength
    Description
    Change and differences in 1-repetition maximum
    Time Frame
    Baseline and weeks 5, 10, 16, 22, 27, 32
    Title
    Muscle force-velocity profiling
    Description
    Change and differences in force (N) and velocity (m/s) derived from a 10-repetition FV-test
    Time Frame
    Baseline and weeks 5, 10, 16, 22, 27, 32
    Other Pre-specified Outcome Measures:
    Title
    Skeletal muscle stiffness
    Description
    Change and differences in skeletal muscle stiffness measured by shear wave ultrasonography
    Time Frame
    Baseline and weeks 10, 22, 32
    Title
    Skeletal muscle tissue characteristics
    Description
    Change and differences in skeletal muscle tissue characteristics determined by immunohistochemistry of muscle biopsies
    Time Frame
    Baseline and weeks 10, 22, 32
    Title
    Bone mineral density
    Description
    Change and differences in bone mineral density (g/cm2) measured by DEXA
    Time Frame
    Baseline and weeks 10, 22, 32
    Title
    Bone health
    Description
    Change and differences in bone health determined by bone health biomarkers in blood
    Time Frame
    Baseline and weeks 10, 22, 32
    Title
    Blood parameters
    Description
    Change and differences in steroid hormones in blood (testosterone, androstenediol, estradiol, and other relevant steroid markers, reproductive hormones (LH, FSH), binding protein (SHBG), cholesterol (total cholesterol, LDL, HDL), and PSA level, and endocrine biomarkers (IGF-1 and P-III-NP).
    Time Frame
    Baseline and weeks 10, 22, 32
    Title
    Aging males symptoms
    Description
    Change and differences in Aging male symptoms score (1="none", 5="extremely severe")
    Time Frame
    Baseline and weeks 5, 10, 16, 22, 27, 32
    Title
    Well-being
    Description
    Change and differences in WHO5 well-being index score (0="at not time", 5="all of the time")
    Time Frame
    Baseline and weeks 5, 10, 16, 22, 27, 32
    Title
    Psychological distress
    Description
    Change and differences in SCL-10 symptoms score (1="not at all", 4="extremely")
    Time Frame
    Baseline and weeks 5, 10, 16, 22, 27, 32
    Title
    Fatigue
    Description
    Change and differences in shortened fatigue questionnaire score (1="yes, that is true", 7="no, that is not true")
    Time Frame
    Baseline and weeks 5, 10, 16, 22, 27, 32
    Title
    Sleep
    Description
    Change and differences in Jenkins sleep scale score (0="not at all", 5="22-31days")
    Time Frame
    Baseline and weeks 5, 10, 16, 22, 27, 32
    Title
    Sexual function
    Description
    Change and differences in sexual function score (items from Health-related quality of life (HRQOL) questionnaire), (
    Time Frame
    Baseline and weeks 5, 10, 16, 22, 27, 32
    Title
    Body perception
    Description
    Change and differences in Body Perception Questionnaire very short form score (1=never, 5=always)
    Time Frame
    Baseline and weeks 5, 10, 16, 22, 27, 32
    Title
    Anger
    Description
    Change and differences in The State Anger subscale of STAXI-2score (0="not at all", 3="very much")
    Time Frame
    Baseline and weeks 5, 10, 16, 22, 27, 32
    Title
    Mania
    Description
    Change and differences in Altman Self-Rating Mania Scale (ASRM) score
    Time Frame
    Baseline and weeks 5, 10, 16, 22, 27, 32
    Title
    Suicide thoughts
    Description
    Change and differences in Suicide thoughts from Montgomery and Åsberg Depression Rating Scale
    Time Frame
    Baseline and weeks 5, 10, 16, 22, 27, 32
    Title
    Cognitive function
    Description
    Change and differences in cognitive function measured by rapid visual information processing
    Time Frame
    Baseline and weeks 5, 10, 16, 22, 27, 32
    Title
    Raadiness to train
    Description
    Change and differences in readiness to train questionnaire score
    Time Frame
    Baseline and weekly up to week 10, and weekly from week 22 up to week 32
    Title
    Exercise effort
    Description
    Change and differences in rating of perceived exertion for effort (Borg CR-10 RPE)
    Time Frame
    Baseline and weekly up to week 10, and weekly from week 22 up to week 32
    Title
    Exercise discomfort
    Description
    Change and differences in rating of perceived exertion for discomfort (sRPD) score
    Time Frame
    Baseline and weekly up to week 10, and weekly from week 22 up to week 32
    Title
    Session pleasure and displeasure
    Description
    Change and differences in perceived pleasure/displeasure with the training session using the pleasure/displeasure feeling scale (sPDF), (-5=very bad", 5="very good")
    Time Frame
    Baseline and weekly up to week 10, and weekly from week 22 up to week 32
    Title
    Exercise enjoyment
    Description
    Change and differences in exercise enjoyment scale score (1="not at all", 7=extraordinary")
    Time Frame
    Baseline and weekly up to week 10, and weekly from week 22 up to week 32

    10. Eligibility

    Sex
    Male
    Minimum Age & Unit of Time
    55 Years
    Maximum Age & Unit of Time
    70 Years
    Accepts Healthy Volunteers
    Accepts Healthy Volunteers
    Eligibility Criteria
    Inclusion Criteria: Sedentary males 55-70 years old Serum testosterone levels >8 nmol/L measured in the morning Without any known illness, disease or other conditions Undergone screening through medical questionnaire, physical examination, routine blood tests and urine sample Written informed consent received Exclusion Criteria: Current or previous participation in a formal exercise regime A BMI < 18 or > 30 kg·m2 Active cardiovascular disease: uncontrolled hypertension (BP > 160/100 mmHg), angina, heart failure (class III/IV), arrhythmia, right to left cardiac shunt, recent cardiac event Family history of early (<55y) death from cardiovascular disease Haematocrit >50% Malignancy Prostate-specific antigen (PSA) >4 ng/mL Lower urinary tract symptoms Taking beta-adrenergic blocking agents, statins, non-steroidal anti-inflammatory drugs Cerebrovascular disease: previous stroke, aneurysm (large vessel or intracranial), epilepsy Respiratory diseases including: pulmonary hypertension, chronic obstructive pulmanary disease (COPD), asthma, sleep apnoea Metabolic disease: hyper and hypo parathyroidism, untreated hyper and hypothyroidism, Cushing's disease, type 1 or 2 diabetes Active inflammatory bowel or renal disease Current or previous steroid treatment or hormone replacement therapy Clotting dysfunction Musculoskeletal or neurological disorders Alcohol or drug abuse

    12. IPD Sharing Statement

    Plan to Share IPD
    No
    IPD Sharing Plan Description
    No identifiable information will be included in any publication. Genome-Wide DNA Methylation and Gene Expression will be deposited with full open access on Gene Expression Omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo/) an internationally recognised database. GEO data derived from human samples will be anonymous, with no identifiable information. GEO data will be deposited at the same time as a publication. All non-identifiable results from the project will be ultimately published in peer-reviewed journals. In addition, all image files, raw excel/ .csv / txt /word files for any of the other analyses described above in the methods will be available as either supplementary files on the publisher's website or fully accessible on request to the corresponding author/authors.
    Citations:
    PubMed Identifier
    24167222
    Citation
    Egner IM, Bruusgaard JC, Eftestol E, Gundersen K. A cellular memory mechanism aids overload hypertrophy in muscle long after an episodic exposure to anabolic steroids. J Physiol. 2013 Dec 15;591(24):6221-30. doi: 10.1113/jphysiol.2013.264457. Epub 2013 Oct 28.
    Results Reference
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    PubMed Identifier
    29382913
    Citation
    Seaborne RA, Strauss J, Cocks M, Shepherd S, O'Brien TD, van Someren KA, Bell PG, Murgatroyd C, Morton JP, Stewart CE, Sharples AP. Human Skeletal Muscle Possesses an Epigenetic Memory of Hypertrophy. Sci Rep. 2018 Jan 30;8(1):1898. doi: 10.1038/s41598-018-20287-3.
    Results Reference
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    PubMed Identifier
    30862794
    Citation
    Turner DC, Seaborne RA, Sharples AP. Comparative Transcriptome and Methylome Analysis in Human Skeletal Muscle Anabolism, Hypertrophy and Epigenetic Memory. Sci Rep. 2019 Mar 12;9(1):4251. doi: 10.1038/s41598-019-40787-0.
    Results Reference
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    PubMed Identifier
    37154489
    Citation
    Sharples AP, Turner DC. Skeletal muscle memory. Am J Physiol Cell Physiol. 2023 Jun 1;324(6):C1274-C1294. doi: 10.1152/ajpcell.00099.2023. Epub 2023 May 8.
    Results Reference
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    PubMed Identifier
    31568675
    Citation
    Gharahdaghi N, Rudrappa S, Brook MS, Idris I, Crossland H, Hamrock C, Abdul Aziz MH, Kadi F, Tarum J, Greenhaff PL, Constantin-Teodosiu D, Cegielski J, Phillips BE, Wilkinson DJ, Szewczyk NJ, Smith K, Atherton PJ. Testosterone therapy induces molecular programming augmenting physiological adaptations to resistance exercise in older men. J Cachexia Sarcopenia Muscle. 2019 Dec;10(6):1276-1294. doi: 10.1002/jcsm.12472. Epub 2019 Sep 30.
    Results Reference
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    PubMed Identifier
    26349924
    Citation
    Sharples AP, Polydorou I, Hughes DC, Owens DJ, Hughes TM, Stewart CE. Skeletal muscle cells possess a 'memory' of acute early life TNF-alpha exposure: role of epigenetic adaptation. Biogerontology. 2016 Jun;17(3):603-17. doi: 10.1007/s10522-015-9604-x. Epub 2015 Sep 8.
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    PubMed Identifier
    34870208
    Citation
    Wen Y, Dungan CM, Mobley CB, Valentino T, von Walden F, Murach KA. Nucleus Type-Specific DNA Methylomics Reveals Epigenetic "Memory" of Prior Adaptation in Skeletal Muscle. Function (Oxf). 2021 Aug 5;2(5):zqab038. doi: 10.1093/function/zqab038. eCollection 2021.
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