Does Human Skeletal Muscle Possess an Epigenetic Memory of Testosterone?

Healthy Aging Clinical Trial

Official title:

Does Human Skeletal Muscle Possess an Epigenetic Memory of Testosterone?

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05964920
• Other study ID #: TESTO-MEM
• Status: Not yet recruiting
• Phase: Phase 2/Phase 3
• Start date: January 1, 2024
• Est. completion date: July 30, 2025

Study information

• Verified date: November 2023
• Source: Norwegian School of Sport Sciences
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 40
• Est. completion date: July 30, 2025
• Est. primary completion date: July 30, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 55 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Age-Related Sarcopenia
• Healthy Aging
• Sarcopenia
• Testosterone Deficiency

Intervention

Drug:
• Saline
Two placebo injections one at baseline and one week 3.
• Testosterone Undecanoate
Two testosterone undecanoate injections, 1000 mg/4 ml at baseline, 500 mg/2 ml at week 3.
• Saline + Resistance exercise training
Two placebo injections one at baseline and one week 3 and10 weeks of supervised, structured, progressive resistance training.
• Testosterone Undecanoate + Resistance exercise training
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.

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Norwegian School of Sport Sciences	Oslo University Hospital

References & 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Skeletal muscle stiffness	Change and differences in skeletal muscle stiffness measured by shear wave ultrasonography	Baseline and weeks 10, 22, 32
Other	Skeletal muscle tissue characteristics	Change and differences in skeletal muscle tissue characteristics determined by immunohistochemistry of muscle biopsies	Baseline and weeks 10, 22, 32
Other	Bone mineral density	Change and differences in bone mineral density (g/cm2) measured by DEXA	Baseline and weeks 10, 22, 32
Other	Bone health	Change and differences in bone health determined by bone health biomarkers in blood	Baseline and weeks 10, 22, 32
Other	Blood parameters	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).	Baseline and weeks 10, 22, 32
Other	Aging males symptoms	Change and differences in Aging male symptoms score (1="none", 5="extremely severe")	Baseline and weeks 5, 10, 16, 22, 27, 32
Other	Well-being	Change and differences in WHO5 well-being index score (0="at not time", 5="all of the time")	Baseline and weeks 5, 10, 16, 22, 27, 32
Other	Psychological distress	Change and differences in SCL-10 symptoms score (1="not at all", 4="extremely")	Baseline and weeks 5, 10, 16, 22, 27, 32
Other	Fatigue	Change and differences in shortened fatigue questionnaire score (1="yes, that is true", 7="no, that is not true")	Baseline and weeks 5, 10, 16, 22, 27, 32
Other	Sleep	Change and differences in Jenkins sleep scale score (0="not at all", 5="22-31days")	Baseline and weeks 5, 10, 16, 22, 27, 32
Other	Sexual function	Change and differences in sexual function score (items from Health-related quality of life (HRQOL) questionnaire), (	Baseline and weeks 5, 10, 16, 22, 27, 32
Other	Body perception	Change and differences in Body Perception Questionnaire very short form score (1=never, 5=always)	Baseline and weeks 5, 10, 16, 22, 27, 32
Other	Anger	Change and differences in The State Anger subscale of STAXI-2score (0="not at all", 3="very much")	Baseline and weeks 5, 10, 16, 22, 27, 32
Other	Mania	Change and differences in Altman Self-Rating Mania Scale (ASRM) score	Baseline and weeks 5, 10, 16, 22, 27, 32
Other	Suicide thoughts	Change and differences in Suicide thoughts from Montgomery and Åsberg Depression Rating Scale	Baseline and weeks 5, 10, 16, 22, 27, 32
Other	Cognitive function	Change and differences in cognitive function measured by rapid visual information processing	Baseline and weeks 5, 10, 16, 22, 27, 32
Other	Raadiness to train	Change and differences in readiness to train questionnaire score	Baseline and weekly up to week 10, and weekly from week 22 up to week 32
Other	Exercise effort	Change and differences in rating of perceived exertion for effort (Borg CR-10 RPE)	Baseline and weekly up to week 10, and weekly from week 22 up to week 32
Other	Exercise discomfort	Change and differences in rating of perceived exertion for discomfort (sRPD) score	Baseline and weekly up to week 10, and weekly from week 22 up to week 32
Other	Session pleasure and displeasure	Change and differences in perceived pleasure/displeasure with the training session using the pleasure/displeasure feeling scale (sPDF), (-5=very bad", 5="very good")	Baseline and weekly up to week 10, and weekly from week 22 up to week 32
Other	Exercise enjoyment	Change and differences in exercise enjoyment scale score (1="not at all", 7=extraordinary")	Baseline and weekly up to week 10, and weekly from week 22 up to week 32
Primary	Fat-free mass	Change and differences in fat-free mass (g) measured by dual x-ray absorptiometry (DEXA).	Baseline and weeks 10, 22, 32
Primary	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
Primary	Skeletal muscle fibre CSA	Change and differences in skeletal muscle fibre CSA measure determined by immunohistochemistry	Baseline and weeks 10, 22, 32
Secondary	DNA methylation in skeletal muscle and blood	Methylation measured in difference/fold change values relative to appropriate controls.	Baseline and weeks 10, 22, 32
Secondary	Gene expression in skeletal muscle and blood	Gene expression measured in difference/fold change values relative to appropriate controls.	Baseline and weeks 10, 22, 32
Secondary	Myonuclei	Change and differences in number of myonuclei determined by immunohistochemistry	Baseline and weeks 10, 22, 32
Secondary	Satellite cells	Change and differences in number of satellite cells determined by immunohistochemistry	Baseline and weeks 10, 22, 32
Secondary	Isometric muscle strength	Change and differences in peak muscle strength (N) using isokinetic dynamometry	Baseline and weeks 5, 10, 16, 22, 27, 32
Secondary	Dynamic muscle strength	Change and differences in 1-repetition maximum	Baseline and weeks 5, 10, 16, 22, 27, 32
Secondary	Muscle force-velocity profiling	Change and differences in force (N) and velocity (m/s) derived from a 10-repetition FV-test	Baseline and weeks 5, 10, 16, 22, 27, 32