Does Human Skeletal Muscle Possess an Epigenetic Memory of Testosterone?

NCT05964920 | Completed Phase 2 DMC

• 1 other identifier: TESTO-MEM
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 1

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.

Conditions

Healthy Aging; Age-Related Sarcopenia; Testosterone Deficiency

Keywords

Healthy aging; Preventing Age-related Sarcopenia; Overcoming Anabolic Resistance; Anti-Doping

Outcome Measures

Primary Outcomes (3)

• Fat-free mass

  Change and differences in fat-free mass (g) measured by dual x-ray absorptiometry (DEXA).

  Baseline and weeks 10, 22, 32

• Skeletal muscle size and cross-sectional area (CSA)

  Change and differences in skeletal muscle size and CSA measured by ultrasound

  Baseline and week 5,10, 16, 22, 27, 32

• Skeletal muscle fibre CSA

  Change and differences in skeletal muscle fibre CSA measure determined by immunohistochemistry

  Baseline and weeks 10, 22, 32

Secondary Outcomes (7)

• DNA methylation in skeletal muscle and blood

  Baseline and weeks 10, 22, 32

• Gene expression in skeletal muscle and blood

  Baseline and weeks 10, 22, 32

• Myonuclei

  Baseline and weeks 10, 22, 32

• Satellite cells

  Baseline and weeks 10, 22, 32

• Isometric muscle strength

  Baseline and weeks 5, 10, 16, 22, 27, 32

Other Outcomes (23)

• Skeletal muscle stiffness

  Baseline and weeks 10, 22, 32

• Skeletal muscle tissue characteristics

  Baseline and weeks 10, 22, 32

• Bone mineral density

  Baseline and weeks 10, 22, 32

Study Arms (4)

Placebo

PLACEBO COMPARATOR

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: 1. Baseline (week 0) 2. Treatment period (week 10) 3. Detraining and placebo abstinence (week 22) 4. Retraining (week 32)

Drug: Saline

Testosterone Undecanoate

EXPERIMENTAL

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: 1. Baseline (week 0) 2. Treatment period (week 10) 3. Detraining and testosterone abstinence (week 22) 4. Retraining (week 32)

Drug: Testosterone Undecanoate

Resistance exercise training + Placebo

PLACEBO COMPARATOR

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: 1. Baseline (week 0) 2. Treatment period (week 10) 3. Detraining and placebo abstinence (week 22) 4. Retraining (week 32)

Drug: Saline + Resistance exercise training

Resistance exercise training + Testosterone Undecanoate

EXPERIMENTAL

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: 1. Baseline (week 0) 2. Treatment period (week 10) 3. Detraining and testosterone abstinence (week 22) 4. Retraining (week 32)

Drug: Testosterone Undecanoate + Resistance exercise training

Interventions

Saline DRUG

Two placebo injections one at baseline and one week 3.

Also known as: Placebo

Placebo

Testosterone Undecanoate DRUG

Two testosterone undecanoate injections, 1000 mg/4 ml at baseline, 500 mg/2 ml at week 3.

Also known as: Nebido, Grünenthal (Grünenthal Norway AS)

Testosterone Undecanoate

Saline + Resistance exercise training DRUG

Two placebo injections one at baseline and one week 3 and10 weeks of supervised, structured, progressive resistance training.

Also known as: Placebo + Resistance exercise training

Resistance exercise training + Placebo

Testosterone Undecanoate + Resistance exercise training DRUG

Two testosterone undecanoate injections, 1000 mg/4 ml at baseline, 500 mg/2 ml at week 3 and 10 weeks of supervised, structured, progressive resistance training.

Also known as: Nebido, Grünenthal (Grünenthal Norway AS) + Resistance exercise training

Resistance exercise training + Testosterone Undecanoate

Eligibility Criteria

• Age: 55 Years - 70 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Sedentary males
• 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

You may not qualify if:

• Current or previous participation in a formal exercise regime
• A BMI \< 18 or \> 30 kg·m2
• Hypersensitivity to the study drug or to any of its constituents
• 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

Sponsors & Collaborators

• Norwegian School of Sport Sciences: lead
• Oslo University Hospital: collaborator

Study Sites (1)

Norwegian School of Sport Sciences

Oslo, Oslo County, 0863, Norway

Location

Related Publications (7)

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

MeSH Terms

Interventions

Sodium Chloride; testosterone undecanoate

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: June 16, 2023
• First Posted: July 28, 2023
• Study Start: September 1, 2024
• Primary Completion: December 22, 2025
• Study Completion: February 6, 2026
• Last Updated: March 6, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

NO (1)