Clinical trial The goal of this clinical trial is to learn how muscle weakness and atrophy develop during short periods of arm immobilization and whether a type of exercise called cross-education can help reduce these effects in women at midlife.

The main questions it aims to answer are:

What changes happen in the nervous system that lead to weakness when a wrist is immobilized?

Can training the opposite arm help maintain muscle strength, muscle size, and nervous system function in the immobilized arm?

Researchers will compare women who have their wrist immobilized with or without opposite-arm resistance training.

Participants will:

Wear a wrist cast on one arm for 7 days

Complete strength training with the opposite arm or no training, depending on their group

Attend study visits for strength and nervous system testing

Have non-invasive tests (like magnetic brain stimulation, muscle recordings, and muscle imaging) to measure how the nervous system and muscle responds

This clinical trial employs a two-phase, parallel-group randomized controlled design targeting midlife women (ages 40-65), stratified by menopausal status. Participants will be randomized to either a cross-education training group (TRAIN) or a standard care control group (CONTROL).

Phase 1 (Immobilization and Cross-Education Intervention):

To induce rapid declines in neuromuscular function, participants will undergo unilateral wrist immobilization of the non-dominant arm using a hard cast for 7 days. During this period, the TRAIN group will complete three resistance training sessions with the non-immobilized arm, while the CONTROL group will remain inactive. The intervention protocol emphasizes maximal effort contractions. The protocol was developed from prior laboratory work and proof-of-concept interventions, with the goal of maximizing the cross-education response.

Phase 2 (Rehabilitation and Recovery):

Following cast removal, both groups will complete a 2-week standardized rehabilitation program (3 sessions per week) designed to restore wrist strength and function in the previously immobilized arm. Rehabilitation training includes progressive resistance exercise to target recovery of neuromuscular performance.

Inclusion Criteria:

• Women between 40-65 years of age
• Baseline handgrip strength >16Kg

Exclusion Criteria:

• Personal or family history of blood clots
• Current use of anticoagulant medications
• Neuromuscular or metabolic diseases (e.g., multiple sclerosis, diabetes)
• Arthritis
• Osteoporosis or osteopenia
• History of myocardial infarction within the past year
• Chronic pain ≥3/10 for ≥3 months
• Uncontrolled hypertension (≥140/90 mmHg)
• Upper extremity surgery within the past year
• Use of assistive hand or arm device within the past year
• Fall involving the upper extremities within the past year
• Upper extremity injuries preventing safe participation
• Current use of muscle relaxants, benzodiazepines, or similar drugs
• Smoking within the past 6 months
• History of drug or alcohol abuse within the past year
• Severe anxiety or claustrophobia
• Pregnancy (current or planned)
• Allergies to medical adhesives
• High risk of sarcopenia (per SARC-F)
• Contraindications to TMS or MRI
• Upper-body resistance training within the past 6 months
• Inability/unwillingness to refrain from resistance training during study

De-identified individual participant data (IPD) that underlie the results of publications (e.g., outcome measures, demographics, adverse events) will be deposited in a publicly accessible data repository (Open Science Framework). Data will be available following publication of primary results. Supporting materials, including the study protocol and statistical analysis plan, will also be shared.

Data will be available following publication of primary results.

De-identified individual participant data (IPD) and supporting documents (study protocol, statistical analysis plan) will be available on the Open Science Framework (OSF) repository following publication of primary results. Data will be accessible to all registered OSF users without restriction. Users will be able to download the datasets and associated documentation directly from the project repository page.