xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT05964920</url>
    </required_header>
    <id_info>
      <org_study_id>TESTO-MEM</org_study_id>
      <nct_id>NCT05964920</nct_id>
    </id_info>
    <brief_title>Does Human Skeletal Muscle Possess an Epigenetic Memory of Testosterone?</brief_title>
    <official_title>Does Human Skeletal Muscle Possess an Epigenetic Memory of Testosterone?</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Norwegian School of Sport Sciences</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Oslo University Hospital</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Norwegian School of Sport Sciences</source>
    <oversight_info>
      <has_dmc>Yes</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
      <is_us_export>No</is_us_export>
    </oversight_info>
    <brief_summary>
      <textblock>
        This project's primary aim of this double-blinded, randomised, placebo-controlled trial is to&#xD;
        investigate whether short-term testosterone administration +/- resistance exercise training&#xD;
        induces a muscle memory response that can lead to longer-lasting benefits in aged human&#xD;
        skeletal muscle.&#xD;
  &#xD;
        The investigators will provide older men with the anabolic hormone, testosterone or placebo,&#xD;
        with or without resistance training, followed by a period of testosterone abstinence and&#xD;
        detraining, followed by a subsequent repeated period of resistance training (retraining).&#xD;
        This will help determine if earlier encounters with short-term testosterone administration&#xD;
        can be &quot;remembered&quot; and if adaptation to later retraining can be enhanced as a consequence of&#xD;
        encountering testosterone earlier.&#xD;
      </textblock>
    </brief_summary>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">August 1, 2023</start_date>
    <completion_date type="Anticipated">October 30, 2024</completion_date>
    <primary_completion_date type="Anticipated">June 30, 2024</primary_completion_date>
    <phase>Phase 2/Phase 3</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <primary_purpose>Basic Science</primary_purpose>
      <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Fat-free mass</measure>
      <time_frame>Baseline and weeks 10, 22, 32</time_frame>
      <description>Change and differences in fat-free mass (g) measured by dual x-ray absorptiometry (DEXA).</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Skeletal muscle size and cross-sectional area (CSA)</measure>
      <time_frame>Baseline and week 5,10, 16, 22, 27, 32</time_frame>
      <description>Change and differences in skeletal muscle size and CSA measured by ultrasound</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Skeletal muscle fibre CSA</measure>
      <time_frame>Baseline and weeks 10, 22, 32</time_frame>
      <description>Change and differences in skeletal muscle fibre CSA measure determined by immunohistochemistry</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>DNA methylation in skeletal muscle and blood</measure>
      <time_frame>Baseline and weeks 10, 22, 32</time_frame>
      <description>Methylation measured in difference/fold change values relative to appropriate controls.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Gene expression in skeletal muscle and blood</measure>
      <time_frame>Baseline and weeks 10, 22, 32</time_frame>
      <description>Gene expression measured in difference/fold change values relative to appropriate controls.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Myonuclei</measure>
      <time_frame>Baseline and weeks 10, 22, 32</time_frame>
      <description>Change and differences in number of myonuclei determined by immunohistochemistry</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Satellite cells</measure>
      <time_frame>Baseline and weeks 10, 22, 32</time_frame>
      <description>Change and differences in number of satellite cells determined by immunohistochemistry</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Isometric muscle strength</measure>
      <time_frame>Baseline and weeks 5, 10, 16, 22, 27, 32</time_frame>
      <description>Change and differences in peak muscle strength (N) using isokinetic dynamometry</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Dynamic muscle strength</measure>
      <time_frame>Baseline and weeks 5, 10, 16, 22, 27, 32</time_frame>
      <description>Change and differences in 1-repetition maximum</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Muscle force-velocity profiling</measure>
      <time_frame>Baseline and weeks 5, 10, 16, 22, 27, 32</time_frame>
      <description>Change and differences in force (N) and velocity (m/s) derived from a 10-repetition FV-test</description>
    </secondary_outcome>
    <other_outcome>
      <measure>Skeletal muscle stiffness</measure>
      <time_frame>Baseline and weeks 10, 22, 32</time_frame>
      <description>Change and differences in skeletal muscle stiffness measured by shear wave ultrasonography</description>
    </other_outcome>
    <other_outcome>
      <measure>Skeletal muscle tissue characteristics</measure>
      <time_frame>Baseline and weeks 10, 22, 32</time_frame>
      <description>Change and differences in skeletal muscle tissue characteristics determined by immunohistochemistry of muscle biopsies</description>
    </other_outcome>
    <other_outcome>
      <measure>Bone mineral density</measure>
      <time_frame>Baseline and weeks 10, 22, 32</time_frame>
      <description>Change and differences in bone mineral density (g/cm2) measured by DEXA</description>
    </other_outcome>
    <other_outcome>
      <measure>Bone health</measure>
      <time_frame>Baseline and weeks 10, 22, 32</time_frame>
      <description>Change and differences in bone health determined by bone health biomarkers in blood</description>
    </other_outcome>
    <other_outcome>
      <measure>Blood parameters</measure>
      <time_frame>Baseline and weeks 10, 22, 32</time_frame>
      <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).</description>
    </other_outcome>
    <other_outcome>
      <measure>Aging males symptoms</measure>
      <time_frame>Baseline and weeks 5, 10, 16, 22, 27, 32</time_frame>
      <description>Change and differences in Aging male symptoms score (1=&quot;none&quot;, 5=&quot;extremely severe&quot;)</description>
    </other_outcome>
    <other_outcome>
      <measure>Well-being</measure>
      <time_frame>Baseline and weeks 5, 10, 16, 22, 27, 32</time_frame>
      <description>Change and differences in WHO5 well-being index score (0=&quot;at not time&quot;, 5=&quot;all of the time&quot;)</description>
    </other_outcome>
    <other_outcome>
      <measure>Psychological distress</measure>
      <time_frame>Baseline and weeks 5, 10, 16, 22, 27, 32</time_frame>
      <description>Change and differences in SCL-10 symptoms score (1=&quot;not at all&quot;, 4=&quot;extremely&quot;)</description>
    </other_outcome>
    <other_outcome>
      <measure>Fatigue</measure>
      <time_frame>Baseline and weeks 5, 10, 16, 22, 27, 32</time_frame>
      <description>Change and differences in shortened fatigue questionnaire score (1=&quot;yes, that is true&quot;, 7=&quot;no, that is not true&quot;)</description>
    </other_outcome>
    <other_outcome>
      <measure>Sleep</measure>
      <time_frame>Baseline and weeks 5, 10, 16, 22, 27, 32</time_frame>
      <description>Change and differences in Jenkins sleep scale score (0=&quot;not at all&quot;, 5=&quot;22-31days&quot;)</description>
    </other_outcome>
    <other_outcome>
      <measure>Sexual function</measure>
      <time_frame>Baseline and weeks 5, 10, 16, 22, 27, 32</time_frame>
      <description>Change and differences in sexual function score (items from Health-related quality of life (HRQOL) questionnaire), (</description>
    </other_outcome>
    <other_outcome>
      <measure>Body perception</measure>
      <time_frame>Baseline and weeks 5, 10, 16, 22, 27, 32</time_frame>
      <description>Change and differences in Body Perception Questionnaire very short form score (1=never, 5=always)</description>
    </other_outcome>
    <other_outcome>
      <measure>Anger</measure>
      <time_frame>Baseline and weeks 5, 10, 16, 22, 27, 32</time_frame>
      <description>Change and differences in The State Anger subscale of STAXI-2score (0=&quot;not at all&quot;, 3=&quot;very much&quot;)</description>
    </other_outcome>
    <other_outcome>
      <measure>Mania</measure>
      <time_frame>Baseline and weeks 5, 10, 16, 22, 27, 32</time_frame>
      <description>Change and differences in Altman Self-Rating Mania Scale (ASRM) score</description>
    </other_outcome>
    <other_outcome>
      <measure>Suicide thoughts</measure>
      <time_frame>Baseline and weeks 5, 10, 16, 22, 27, 32</time_frame>
      <description>Change and differences in Suicide thoughts from Montgomery and Åsberg Depression Rating Scale</description>
    </other_outcome>
    <other_outcome>
      <measure>Cognitive function</measure>
      <time_frame>Baseline and weeks 5, 10, 16, 22, 27, 32</time_frame>
      <description>Change and differences in cognitive function measured by rapid visual information processing</description>
    </other_outcome>
    <other_outcome>
      <measure>Raadiness to train</measure>
      <time_frame>Baseline and weekly up to week 10, and weekly from week 22 up to week 32</time_frame>
      <description>Change and differences in readiness to train questionnaire score</description>
    </other_outcome>
    <other_outcome>
      <measure>Exercise effort</measure>
      <time_frame>Baseline and weekly up to week 10, and weekly from week 22 up to week 32</time_frame>
      <description>Change and differences in rating of perceived exertion for effort (Borg CR-10 RPE)</description>
    </other_outcome>
    <other_outcome>
      <measure>Exercise discomfort</measure>
      <time_frame>Baseline and weekly up to week 10, and weekly from week 22 up to week 32</time_frame>
      <description>Change and differences in rating of perceived exertion for discomfort (sRPD) score</description>
    </other_outcome>
    <other_outcome>
      <measure>Session pleasure and displeasure</measure>
      <time_frame>Baseline and weekly up to week 10, and weekly from week 22 up to week 32</time_frame>
      <description>Change and differences in perceived pleasure/displeasure with the training session using the pleasure/displeasure feeling scale (sPDF), (-5=very bad&quot;, 5=&quot;very good&quot;)</description>
    </other_outcome>
    <other_outcome>
      <measure>Exercise enjoyment</measure>
      <time_frame>Baseline and weekly up to week 10, and weekly from week 22 up to week 32</time_frame>
      <description>Change and differences in exercise enjoyment scale score (1=&quot;not at all&quot;, 7=extraordinary&quot;)</description>
    </other_outcome>
    <number_of_arms>4</number_of_arms>
    <enrollment type="Anticipated">40</enrollment>
    <condition>Healthy Aging</condition>
    <condition>Age-Related Sarcopenia</condition>
    <condition>Testosterone Deficiency</condition>
    <arm_group>
      <arm_group_label>Placebo</arm_group_label>
      <arm_group_type>Placebo Comparator</arm_group_type>
      <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.&#xD;
  Questionnaires, physiological and psychological measures, skeletal muscle biopsies and blood samples will be taken at time points of:&#xD;
  Baseline (week 0)&#xD;
  Treatment period (week 10)&#xD;
  Detraining and placebo abstinence (week 22)&#xD;
  Retraining (week 32)</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Testosterone Undecanoate</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <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.&#xD;
  Questionnaires, physiological and psychological measures, skeletal muscle biopsies and blood samples will be taken at time points of:&#xD;
  Baseline (week 0)&#xD;
  Treatment period (week 10)&#xD;
  Detraining and testosterone abstinence (week 22)&#xD;
  Retraining (week 32)</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Resistance exercise training + Placebo</arm_group_label>
      <arm_group_type>Placebo Comparator</arm_group_type>
      <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.&#xD;
  Questionnaires, physiological and psychological measures, skeletal muscle biopsies and blood samples will be taken at time points of:&#xD;
  Baseline (week 0)&#xD;
  Treatment period (week 10)&#xD;
  Detraining and placebo abstinence (week 22)&#xD;
  Retraining (week 32)</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Resistance exercise training + Testosterone Undecanoate</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <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.&#xD;
  Questionnaires, physiological and psychological measures, skeletal muscle biopsies and blood samples will be taken at time points of:&#xD;
  Baseline (week 0)&#xD;
  Treatment period (week 10)&#xD;
  Detraining and testosterone abstinence (week 22)&#xD;
  Retraining (week 32)</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Saline</intervention_name>
      <description>Two placebo injections one at baseline and one week 3.</description>
      <arm_group_label>Placebo</arm_group_label>
      <arm_group_label>Resistance exercise training + Placebo</arm_group_label>
      <other_name>Placebo</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Testosterone Undecanoate</intervention_name>
      <description>Two testosterone undecanoate injections, 1000 mg/4 ml at baseline, 500 mg/2 ml at week 3.</description>
      <arm_group_label>Resistance exercise training + Testosterone Undecanoate</arm_group_label>
      <arm_group_label>Testosterone Undecanoate</arm_group_label>
      <other_name>Nebido, Grünenthal (Grünenthal Norway AS)</other_name>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Sedentary males&#xD;
  &#xD;
            -  55-70 years old&#xD;
  &#xD;
            -  Serum testosterone levels &gt;8 nmol/L measured in the morning&#xD;
  &#xD;
            -  Without any known illness, disease or other conditions&#xD;
  &#xD;
            -  Undergone screening through medical questionnaire, physical examination, routine blood&#xD;
               tests and urine sample&#xD;
  &#xD;
            -  Written informed consent received&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Current or previous participation in a formal exercise regime&#xD;
  &#xD;
            -  A BMI &lt; 18 or &gt; 30 kg·m2&#xD;
  &#xD;
            -  Active cardiovascular disease: uncontrolled hypertension (BP &gt; 160/100 mmHg), angina,&#xD;
               heart failure (class III/IV), arrhythmia, right to left cardiac shunt, recent cardiac&#xD;
               event&#xD;
  &#xD;
            -  Family history of early (&lt;55y) death from cardiovascular disease&#xD;
  &#xD;
            -  Haematocrit &gt;50%&#xD;
  &#xD;
            -  Malignancy&#xD;
  &#xD;
            -  Prostate-specific antigen (PSA) &gt;4 ng/mL&#xD;
  &#xD;
            -  Lower urinary tract symptoms&#xD;
  &#xD;
            -  Taking beta-adrenergic blocking agents, statins, non-steroidal anti-inflammatory drugs&#xD;
  &#xD;
            -  Cerebrovascular disease: previous stroke, aneurysm (large vessel or intracranial),&#xD;
               epilepsy&#xD;
  &#xD;
            -  Respiratory diseases including: pulmonary hypertension, chronic obstructive pulmanary&#xD;
               disease (COPD), asthma, sleep apnoea&#xD;
  &#xD;
            -  Metabolic disease: hyper and hypo parathyroidism, untreated hyper and hypothyroidism,&#xD;
               Cushing's disease, type 1 or 2 diabetes&#xD;
  &#xD;
            -  Active inflammatory bowel or renal disease&#xD;
  &#xD;
            -  Current or previous steroid treatment or hormone replacement therapy&#xD;
  &#xD;
            -  Clotting dysfunction&#xD;
  &#xD;
            -  Musculoskeletal or neurological disorders&#xD;
  &#xD;
            -  Alcohol or drug abuse&#xD;
        </textblock>
      </criteria>
      <gender>Male</gender>
      <minimum_age>55 Years</minimum_age>
      <maximum_age>70 Years</maximum_age>
      <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
    </eligibility>
    <reference>
      <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.</citation>
      <PMID>24167222</PMID>
    </reference>
    <reference>
      <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.</citation>
      <PMID>29382913</PMID>
    </reference>
    <reference>
      <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.</citation>
      <PMID>30862794</PMID>
    </reference>
    <reference>
      <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.</citation>
      <PMID>37154489</PMID>
    </reference>
    <reference>
      <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.</citation>
      <PMID>31568675</PMID>
    </reference>
    <reference>
      <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.</citation>
      <PMID>26349924</PMID>
    </reference>
    <reference>
      <citation>Wen Y, Dungan CM, Mobley CB, Valentino T, von Walden F, Murach KA. Nucleus Type-Specific DNA Methylomics Reveals Epigenetic &quot;Memory&quot; of Prior Adaptation in Skeletal Muscle. Function (Oxf). 2021 Aug 5;2(5):zqab038. doi: 10.1093/function/zqab038. eCollection 2021.</citation>
      <PMID>34870208</PMID>
    </reference>
    <verification_date>July 2023</verification_date>
    <study_first_submitted>June 16, 2023</study_first_submitted>
    <study_first_submitted_qc>July 19, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">July 28, 2023</study_first_posted>
    <last_update_submitted>July 19, 2023</last_update_submitted>
    <last_update_submitted_qc>July 19, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">July 28, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Norwegian School of Sport Sciences</investigator_affiliation>
      <investigator_full_name>Adam Sharples</investigator_full_name>
      <investigator_title>Professor</investigator_title>
    </responsible_party>
    <keyword>Healthy aging</keyword>
    <keyword>Preventing Age-related Sarcopenia</keyword>
    <keyword>Overcoming Anabolic Resistance</keyword>
    <keyword>Anti-Doping</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Sarcopenia</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Methyltestosterone</mesh_term>
      <mesh_term>Testosterone</mesh_term>
      <mesh_term>Testosterone undecanoate</mesh_term>
      <mesh_term>Testosterone enanthate</mesh_term>
      <mesh_term>Testosterone 17 beta-cypionate</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
      <ipd_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.</ipd_description>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT05964920
  org study id: TESTO-MEM
  nct id: NCT05964920
  lead sponsor: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  is us export: No
  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.
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Basic Science
  masking: Triple (Participant, Investigator, Outcomes Assessor)
  measure: Fat-free mass
  time frame: Baseline and weeks 10, 22, 32
  description: Change and differences in fat-free mass (g) measured by dual x-ray absorptiometry (DEXA).
  measure: Skeletal muscle size and cross-sectional area (CSA)
  time frame: Baseline and week 5,10, 16, 22, 27, 32
  description: Change and differences in skeletal muscle size and CSA measured by ultrasound
  measure: Skeletal muscle fibre CSA
  time frame: Baseline and weeks 10, 22, 32
  description: Change and differences in skeletal muscle fibre CSA measure determined by immunohistochemistry
  measure: DNA methylation in skeletal muscle and blood
  time frame: Baseline and weeks 10, 22, 32
  description: Methylation measured in difference/fold change values relative to appropriate controls.
  measure: Gene expression in skeletal muscle and blood
  time frame: Baseline and weeks 10, 22, 32
  description: Gene expression measured in difference/fold change values relative to appropriate controls.
  measure: Myonuclei
  time frame: Baseline and weeks 10, 22, 32
  description: Change and differences in number of myonuclei determined by immunohistochemistry
  measure: Satellite cells
  time frame: Baseline and weeks 10, 22, 32
  description: Change and differences in number of satellite cells determined by immunohistochemistry
  measure: Isometric muscle strength
  time frame: Baseline and weeks 5, 10, 16, 22, 27, 32
  description: Change and differences in peak muscle strength (N) using isokinetic dynamometry
  measure: Dynamic muscle strength
  time frame: Baseline and weeks 5, 10, 16, 22, 27, 32
  description: Change and differences in 1-repetition maximum
  measure: Muscle force-velocity profiling
  time frame: Baseline and weeks 5, 10, 16, 22, 27, 32
  description: Change and differences in force (N) and velocity (m/s) derived from a 10-repetition FV-test
  measure: Skeletal muscle stiffness
  time frame: Baseline and weeks 10, 22, 32
  description: Change and differences in skeletal muscle stiffness measured by shear wave ultrasonography
  measure: Skeletal muscle tissue characteristics
  time frame: Baseline and weeks 10, 22, 32
  description: Change and differences in skeletal muscle tissue characteristics determined by immunohistochemistry of muscle biopsies
  measure: Bone mineral density
  time frame: Baseline and weeks 10, 22, 32
  description: Change and differences in bone mineral density (g/cm2) measured by DEXA
  measure: Bone health
  time frame: Baseline and weeks 10, 22, 32
  description: Change and differences in bone health determined by bone health biomarkers in blood
  measure: Blood parameters
  time frame: Baseline and weeks 10, 22, 32
  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).
  measure: Aging males symptoms
  time frame: Baseline and weeks 5, 10, 16, 22, 27, 32
  description: Change and differences in Aging male symptoms score (1="none", 5="extremely severe")
  measure: Well-being
  time frame: Baseline and weeks 5, 10, 16, 22, 27, 32
  description: Change and differences in WHO5 well-being index score (0="at not time", 5="all of the time")
  measure: Psychological distress
  time frame: Baseline and weeks 5, 10, 16, 22, 27, 32
  description: Change and differences in SCL-10 symptoms score (1="not at all", 4="extremely")
  measure: Fatigue
  time frame: Baseline and weeks 5, 10, 16, 22, 27, 32
  description: Change and differences in shortened fatigue questionnaire score (1="yes, that is true", 7="no, that is not true")
  measure: Sleep
  time frame: Baseline and weeks 5, 10, 16, 22, 27, 32
  description: Change and differences in Jenkins sleep scale score (0="not at all", 5="22-31days")
  measure: Sexual function
  time frame: Baseline and weeks 5, 10, 16, 22, 27, 32
  description: Change and differences in sexual function score (items from Health-related quality of life (HRQOL) questionnaire), (
  measure: Body perception
  time frame: Baseline and weeks 5, 10, 16, 22, 27, 32
  description: Change and differences in Body Perception Questionnaire very short form score (1=never, 5=always)
  measure: Anger
  time frame: Baseline and weeks 5, 10, 16, 22, 27, 32
  description: Change and differences in The State Anger subscale of STAXI-2score (0="not at all", 3="very much")
  measure: Mania
  time frame: Baseline and weeks 5, 10, 16, 22, 27, 32
  description: Change and differences in Altman Self-Rating Mania Scale (ASRM) score
  measure: Suicide thoughts
  time frame: Baseline and weeks 5, 10, 16, 22, 27, 32
  description: Change and differences in Suicide thoughts from Montgomery and Åsberg Depression Rating Scale
  measure: Cognitive function
  time frame: Baseline and weeks 5, 10, 16, 22, 27, 32
  description: Change and differences in cognitive function measured by rapid visual information processing
  measure: Raadiness to train
  time frame: Baseline and weekly up to week 10, and weekly from week 22 up to week 32
  description: Change and differences in readiness to train questionnaire score
  measure: Exercise effort
  time frame: Baseline and weekly up to week 10, and weekly from week 22 up to week 32
  description: Change and differences in rating of perceived exertion for effort (Borg CR-10 RPE)
  measure: Exercise discomfort
  time frame: Baseline and weekly up to week 10, and weekly from week 22 up to week 32
  description: Change and differences in rating of perceived exertion for discomfort (sRPD) score
  measure: Session pleasure and displeasure
  time frame: Baseline and weekly up to week 10, and weekly from week 22 up to week 32
  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")
  measure: Exercise enjoyment
  time frame: Baseline and weekly up to week 10, and weekly from week 22 up to week 32
  description: Change and differences in exercise enjoyment scale score (1="not at all", 7=extraordinary")
  arm group label: Placebo
  arm group type: Placebo Comparator
  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 group label: Testosterone Undecanoate
  arm group type: Experimental
  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 group label: Resistance exercise training + Placebo
  arm group type: Placebo Comparator
  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 group label: Resistance exercise training + Testosterone Undecanoate
  arm group type: Experimental
  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: Saline
  description: Two placebo injections one at baseline and one week 3.
  arm group label: Placebo
  arm group label: Resistance exercise training + Placebo
  other name: Placebo
  intervention type: Drug
  intervention name: Testosterone Undecanoate
  description: Two testosterone undecanoate injections, 1000 mg/4 ml at baseline, 500 mg/2 ml at week 3.
  arm group label: Resistance exercise training + Testosterone Undecanoate
  arm group label: Testosterone Undecanoate
  other name: Nebido, Grünenthal (Grünenthal Norway AS)
  criteria: 
  gender: Male
  minimum age: 55 Years
  maximum age: 70 Years
  healthy volunteers: Accepts Healthy Volunteers
  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.
  PMID: 24167222
  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.
  PMID: 29382913
  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.
  PMID: 30862794
  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.
  PMID: 37154489
  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.
  PMID: 31568675
  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.
  PMID: 26349924
  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.
  PMID: 34870208
  responsible party type: Principal Investigator
  investigator affiliation: Norwegian School of Sport Sciences
  investigator full name: Adam Sharples
  investigator title: Professor
  mesh term: Sarcopenia
  mesh term: Methyltestosterone
  mesh term: Testosterone
  mesh term: Testosterone undecanoate
  mesh term: Testosterone enanthate
  mesh term: Testosterone 17 beta-cypionate
  sharing ipd: No
  ipd 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.