Clinical trial NCT05964920: 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
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Healthy Aging
Age-Related Sarcopenia
Testosterone Deficiency
Keywords: Healthy aging
Preventing Age-related Sarcopenia
Overcoming Anabolic Resistance
Anti-Doping
Lead sponsor: Norwegian School of Sport Sciences
Sponsor class: OTHER
Collaborators: name: Oslo University Hospital
First posted: 2023-07-28
Enrollment: 40
Sex: MALE
Minimum age (years): 55
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.


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
* 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
* Clotting dysfunction
* Musculoskeletal or neurological disorders
* Alcohol or drug abuse
* Receiving oral anticoagulants
* Serum testosterone levels above the reference range for 50 year olds (\>32 nmol/L) (Bjerner et al., 2009) measured in the morning 1

Primary outcomes:
measure: Fat-free mass
timeFrame: Baseline and weeks 10, 22, 32
measure: Skeletal muscle size and cross-sectional area (CSA)
timeFrame: Baseline and week 5,10, 16, 22, 27, 32
measure: Skeletal muscle fibre CSA
timeFrame: Baseline and weeks 10, 22, 32
Secondary outcomes:
measure: DNA methylation in skeletal muscle and blood
timeFrame: Baseline and weeks 10, 22, 32
measure: Gene expression in skeletal muscle and blood
timeFrame: Baseline and weeks 10, 22, 32
measure: Myonuclei
timeFrame: Baseline and weeks 10, 22, 32
measure: Satellite cells
timeFrame: Baseline and weeks 10, 22, 32
measure: Isometric muscle strength
timeFrame: Baseline and weeks 5, 10, 16, 22, 27, 32
measure: Dynamic muscle strength
timeFrame: Baseline and weeks 5, 10, 16, 22, 27, 32
measure: Muscle force-velocity profiling
timeFrame: Baseline and weeks 5, 10, 16, 22, 27, 32
Other outcomes:
measure: Skeletal muscle stiffness
timeFrame: Baseline and weeks 10, 22, 32
measure: Skeletal muscle tissue characteristics
timeFrame: Baseline and weeks 10, 22, 32
measure: Bone mineral density
timeFrame: Baseline and weeks 10, 22, 32
measure: Bone health
timeFrame: Baseline and weeks 10, 22, 32
measure: Blood volume, haemoglobin and lean body mass
timeFrame: Baseline and weeks 10, 22, 32
measure: Blood parameters
timeFrame: Baseline and weeks 10, 22, 32
measure: Aging males symptoms
timeFrame: Baseline and weeks 5, 10, 16, 22, 27, 32
measure: Well-being
timeFrame: Baseline and weeks 5, 10, 16, 22, 27, 32
measure: Psychological distress
timeFrame: Baseline and weeks 5, 10, 16, 22, 27, 32
measure: Fatigue
timeFrame: Baseline and weeks 5, 10, 16, 22, 27, 32
measure: Sleep
timeFrame: Baseline and weeks 5, 10, 16, 22, 27, 32
measure: Sexual function
timeFrame: Baseline and weeks 5, 10, 16, 22, 27, 32
measure: Body perception
timeFrame: Baseline and weeks 5, 10, 16, 22, 27, 32
measure: Anger
timeFrame: Baseline and weeks 5, 10, 16, 22, 27, 32
measure: Mania
timeFrame: Baseline and weeks 5, 10, 16, 22, 27, 32
measure: Suicide thoughts
timeFrame: Baseline and weeks 5, 10, 16, 22, 27, 32
measure: Cognitive function
timeFrame: Baseline and weeks 5, 10, 16, 22, 27, 32
measure: Exercise motivation
timeFrame: Baseline and weekly up to week 10, and weekly from week 22 up to week 32
measure: Exercise effort
timeFrame: Baseline and weekly up to week 10, and weekly from week 22 up to week 32
measure: Exercise discomfort
timeFrame: Baseline and weekly up to week 10, and weekly from week 22 up to week 32
measure: Session pleasure and displeasure
timeFrame: Baseline and weekly up to week 10, and weekly from week 22 up to week 32
measure: Exercise enjoyment
timeFrame: Baseline and weekly up to week 10, and weekly from week 22 up to week 32
measure: Reps in reserve
timeFrame: Baseline and weekly up to week 10, and weekly from week 22 up to week 32
Locations:
city: Oslo
country: Norway
facility: Norwegian School of Sport Sciences
Study officials:
References:
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: 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: 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: 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: 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: 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: 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.