Exercise Intensity and Muscle Recovery in Statin Users

Official title

Investigating the Role of Mechanical Muscle Loading in the Context of Preventive Exercise for Statin Users - a Pilot Study

Overview

This study aims to investigate how different types and intensities of exercise affect muscle recovery in individuals taking statin medications compared to healthy controls. Statins are essential for cardiovascular prevention but are often associated with muscle-related side effects (SAMS), which can be exacerbated by physical activity. The study will compare aerobic cycling (low muscular strain) with resistance training (RT) at increasing intensities (40%, 60%, and 80% of estimated 1-repetition maximum; e1RM). Researchers will measure markers of muscle damage, such as creatine kinase (CK) levels, and subjective recovery needs to determine which exercise modalities and intensities are best tolerated by statin users. The goal is to provide evidence for more individualized and safer exercise recommendations for this population.

Detailed description

Study Design This is a matched-pairs, non-randomized, dose-escalation exercise trial with within-subject replication. Statin users (STN) and statin-naïve controls (CON) are matched by sex, age (±2 years), and body mass index (BMI) (±2 kg/m²). Due to ethical and safety reasons (risk of injury in untrained individuals exposed to high-intensity resistance exercise), the order of experimental periods is fixed: all participants begin with endurance exercise (lowest muscle strain), then progress to resistance training at 40%, 60%, and 80% of e1RM.

Interventions Endurance training sessions (END): 40 minutes cycling at 60% heart rate reserve (HRR), plus 5 min warm-up and cool-down.

Resistance training sessions (RT1-RT3): 8 machine-based exercises (e.g., leg press, chest press, lat pull-down). Two sets per exercise, repetitions decrease with intensity (20 reps at 40% e1RM, 12 reps at 60%, 8 reps at 80%). Rest between sets \~120 sec. Each intensity period includes two identical sessions, separated by a 5-21-day washout.

Procedures Screening: Medical history, physical exam, resting electrocardiogram (ECG), cardiopulmonary exercise test (CPET).

Baseline: Two measurements of CK from capillary blood and pressure pain threshold (PPT) on the rectus femoris.

Familiarization: Two low-intensity RT sessions to teach correct technique and breathing.

10-repetition maximum (10RM) testing: For each RT exercise, participants perform up to three attempts to find the maximal load for 10 controlled repetitions; then e1RM is calculated for intensity prescription.

Experimental periods: Each exercise session is preceded by a pre-exercise capillary CK sample and PPT assessment. Participants return 24h later for post-exercise CK and PPT. Before, during and/or immediately after exercise, heart rate (HR) and blood lactate are recorded. The rating of perceived exertion (RPE) is recorded 10 minutes after exercise. Daily online monitoring of muscle symptoms and recovery needs is performed throughout the study.

Outcome Measures Primary: Change in serum CK from pre- to 24h post-exercise (ΔCK).

Secondary: Change in PPT from pre- to 24h post-exercise (ΔPPT), change in blood lactate pre- to post-exercise, average HR during exercise, session-RPE, subjective recovery need (questionnaire) 24 hours after exercise.

Target Sample Size 40 participants (20 per group).

Statistical Analysis Linear mixed model with fixed effects: medication (statin vs. control), exercise intensity (END, RT1, RT2, RT3), and their interaction (main research question). Pre-exercise values as covariates; random intercept for subject. No time trend included as focus is on acute responses.

Ethics and Data Management All procedures follow preventive exercise guidelines. Participants benefit from supervised training and receive post-study exercise recommendations. Data are pseudonymized, stored within the European Union, and GDPR-compliant. Capillary sampling from the earlobe minimizes risks (only minor swelling/bruising possible).

Study Duration Total data acquisition \<15 months; experimental phase per participant \<4 months.

Interventions

• Other Dose-Escalation Exercise Protocol
  A dose-escalation protocol consisting of END (40 minutes of cycling at 60% HRR) and RT at 40%, 60%, and 80% of e1RM. RT includes 8 machine-based exercises, 2 sets per exercise, with repetitions decreasing as intensity increases (20, 12, and 8 reps respectively). Each intensity period comprises two identical sessions with a 5-21 day washout. All sessions are supervised.

Primary outcome measures

• Change in serum creatine kinase (CK) level from pre-exercise to 24 hours post-exercise [Time frame: Baseline and 24 hours post-exercise]

Secondary outcome measures (5)

• Change in pressure pain threshold (PPT) from pre-exercise to 24 hours post-exercise [Time frame: Baseline and 24 hours post-exercise]
• Heart rate (HR) during exercise [Time frame: Continuous during each exercise session (from the start to the end of each endurance and resistance training session).]
• Blood lactate concentration before and after exercise [Time frame: Before the start and immediately after each endurance and resistance training session.]
• Subjective Need for Recovery after exercise (questionnaire) [Time frame: Questionnaires will be collected daily to enable intra-individual robust scaling. However, the analysis will focus on recovery needs 24 hours post-exercise.]
• Session rating of perceived exertion (RPE) [Time frame: RPE will be measured 10 minutes after the end of each endurance and resistance training session.]

Eligibility criteria

Inclusion criteria

• Sedentary behavior (defined as < 1 hour of planned physical activity per week)
• Low occupational physical activity
• Age between 30 and 65 years
• Non-smoker
• Medical clearance to partake in physical exercise (as determined during screening visit)
• For statin users: Current statin medication with stable dosage for at least 8 weeks prior to enrollment
• For controls: Statin-naïve individuals

Exclusion criteria

• BMI < 20 kg/m² or > 30 kg/m²
• Smoking or smoking cessation < 1 year ago
• Medical conditions or musculoskeletal issues that preclude eligibility for full physical effort or interfere with outcome measures
• Medication (other than statins) that may interfere with physical exercise or outcome measures (assessment on a case-by-case basis during screening visit)
• Any condition identified during screening (e.g., abnormal ECG, cardiopulmonary exercise test) that, in the opinion of the physician, precludes safe participation

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Basic science

Study locations

Austria · 1 center

• University of Innsbruck — Innsbruck

Publications

• Ruscica M, Ferri N, Banach M, Sirtori CR, Corsini A. Side effects of statins: from pathophysiology and epidemiology to diagnostic and therapeutic implications. Cardiovasc Res. 2023 Jan 18;118(17):3288-3304. doi: 10.1093/cvr/cvac020. PMID 35238338
• Sinzinger H, O'Grady J. Professional athletes suffering from familial hypercholesterolaemia rarely tolerate statin treatment because of muscular problems. Br J Clin Pharmacol. 2004 Apr;57(4):525-8. doi: 10.1111/j.1365-2125.2003.02044.x. PMID 15025753
• Hoppstadter J, Valbuena Perez JV, Linnenberger R, Dahlem C, Legroux TM, Hecksteden A, Tse WKF, Flamini S, Andreas A, Herrmann J, Herr C, Muller R, Meyer T, Bals R, Riccardi C, Bruscoli S, Kiemer AK. The glucocorticoid-induced leucine zipper mediates statin-induced muscle damage. FASEB J. 2020 Mar;34(3):4684-4701. doi: 10.1096/fj.201902557RRR. Epub 2020 Feb 6. PMID 32030813
• Hecksteden A, Hoppstadter J, Bizjak DA, Jerg A, Kirsten J, Kruger K, Niess A, Steinacker J, Kiemer AK. Effects of acute exercise and training status on glucocorticoid-induced leucine zipper (GILZ) expression in human skeletal muscle. J Sci Med Sport. 2023 Dec;26(12):707-710. doi: 10.1016/j.jsams.2023.10.007. Epub 2023 Oct 21. PMID 37951824
• Paul S, Donath L, Hoppstadter J, Hecksteden A. Resistance but not endurance training suppresses glucocorticoid-induced leucine zipper (GILZ) expression in human skeletal muscle. Eur J Appl Physiol. 2025 Apr;125(4):1023-1036. doi: 10.1007/s00421-024-05644-7. Epub 2024 Nov 5. PMID 39499305
• Morales-Palomo F, Ramirez-Jimenez M, Ortega JF, Moreno-Cabanas A, Mora-Rodriguez R. Exercise Training Adaptations in Metabolic Syndrome Individuals on Chronic Statin Treatment. J Clin Endocrinol Metab. 2020 Apr 1;105(4):dgz304. doi: 10.1210/clinem/dgz304. PMID 31875915
• Stroes ES, Thompson PD, Corsini A, Vladutiu GD, Raal FJ, Ray KK, Roden M, Stein E, Tokgozoglu L, Nordestgaard BG, Bruckert E, De Backer G, Krauss RM, Laufs U, Santos RD, Hegele RA, Hovingh GK, Leiter LA, Mach F, Marz W, Newman CB, Wiklund O, Jacobson TA, Catapano AL, Chapman MJ, Ginsberg HN; European Atherosclerosis Society Consensus Panel. Statin-associated muscle symptoms: impact on statin thera PMID 25694464
• Mikus CR, Boyle LJ, Borengasser SJ, Oberlin DJ, Naples SP, Fletcher J, Meers GM, Ruebel M, Laughlin MH, Dellsperger KC, Fadel PJ, Thyfault JP. Simvastatin impairs exercise training adaptations. J Am Coll Cardiol. 2013 Aug 20;62(8):709-14. doi: 10.1016/j.jacc.2013.02.074. Epub 2013 Apr 10. PMID 23583255

Identifiers

NCT: NCT07563452 · 1098/2025

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗