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.

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.

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

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