Morphological and Functional Biomarkers of Skeletal Muscle Adaptations in Sarcopenia (EXEDOS)

Morphological and Functional Biomarkers of Skeletal Muscle Adaptations for Early Detection of Sarcopenia and of the Therapeutic Effects of a Home-Based Exercise Intervention: A Randomized-Controlled Trial

Sarcopenia is an age-related condition characterized by progressive loss of skeletal muscle mass, muscle strength, and physical performance. It is associated with frailty, falls, disability, reduced independence, lower quality of life, and increased healthcare burden. Despite its clinical relevance, sarcopenia remains underdiagnosed, partly because current diagnostic approaches may be difficult to implement broadly in clinical practice and may not fully capture early changes in muscle quality and neuromuscular function.

The EXEDOS study aims to evaluate an integrated diagnostic and therapeutic strategy for the early detection and management of sarcopenia. The study will assess Quantitative Ultrasound with Radio-Frequency analysis (QUS-RF) as a non-invasive, accessible, and radiation-free tool to characterize muscle morphology, microstructure, and quality. QUS-RF-derived parameters will be compared with established assessments, including body composition, muscle strength, physical performance, and imaging-based measures, to determine their feasibility, reliability, diagnostic accuracy, and responsiveness to change.

The study also includes a 48-week randomized, parallel-group, open-label superiority trial designed to evaluate the effects of a digitally delivered home-based exercise intervention in older adults with sarcopenia or at risk of sarcopenia. Eligible participants will be randomized to either an experimental group receiving a structured home-based exercise program or a control group receiving general physical activity recommendations in line with current guidelines. The exercise program will combine progressive resistance and aerobic training and will be supported by a digital platform allowing remote monitoring, feedback, and supervision. All participants will receive general nutritional advice.

Assessments will be performed at baseline, Week 12, and Week 48. The primary outcome of the randomized trial will be the change in 30-second Chair Stand Test performance, used as an indicator of lower-limb muscle function. Secondary outcomes will include handgrip strength, lower-limb maximal and explosive strength, walking capacity, balance, body composition, QUS-RF-derived muscle parameters, quality of life, mood, physical activity, dietary indicators, blood biomarkers, adherence to the intervention, and safety. A health economic analysis will also be conducted to estimate the potential cost-effectiveness and cost-utility of the proposed diagnostic and therapeutic strategy.

By combining innovative muscle assessment with a scalable digitally supported exercise intervention, the EXEDOS study aims to improve early sarcopenia detection, personalize exercise prescription, and support the development of sustainable strategies to preserve muscle function and independence in older adults.

Study Overview

• Status: Recruiting
• Conditions: Sarcopenia
• Intervention / Treatment: Behavioral: Digitally delivered home-based exercise intervention; Behavioral: General physical activity recommendations

• Study Type: Interventional
• Enrollment (Estimated): 192
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Matteo Bonato, Ph.D.; Phone Number: +390283502246; Email: matteo.bonato@unimi.it
• Study Contact Backup: Name: Stefano Borghi, Ph.D.; Email: stefano.borghi@grupposandonato.it

Study Locations

• Italy
  • Mi
    • Milan, Mi, Italy, 20157
      • Recruiting
      • IRCCS Ospedale Galeazzi-Sant'Ambrogio
      • Contact: Stefano Borghi, Ph.D.; Phone Number: +390283502246; Email: stefano.borghi@grupposandonato.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Sedentary individuals aged over 50 years.
• Individuals with sarcopenia, defined as reduced muscle mass assessed by bioelectrical impedance analysis and reduced muscle strength assessed by handgrip strength, according to EWGSOP2 criteria.
• Individuals at risk of sarcopenia, defined as reduced muscle mass with preserved muscle strength.
• Healthy age-, sex-, and physical activity-matched older adults eligible for inclusion in the reference cohort.
• Ability to understand the study procedures and provide written informed consent.

Exclusion Criteria:

• Hospitalization within the previous 6 weeks.
• Substance or alcohol abuse.
• Use of medications that may impair balance or coordination.
• Major locomotor impairments.
• Inability to complete the exercise protocol.
• Medical, cognitive, or functional conditions that, in the opinion of the investigators, may interfere with safe participation, adherence to the study procedures, or completion of the follow-up assessments.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sarcopenia - Exercise Intervention; Participants with sarcopenia allocated to the exercise group will receive a 48-week digitally delivered home-based exercise intervention. The program will include progressive resistance exercises using body weight and/or light external loads, combined with moderate-intensity aerobic training. Sessions will be performed three times per week for approximately 45 minutes per session. The intervention will be supported by a digital platform, wearable inertial sensors, heart-rate monitoring, instructional videos, automated feedback, and remote professional supervision. Participants will also receive general nutritional advice.	Behavioral: Digitally delivered home-based exercise intervention; Digitally delivered, home-based, 48-week exercise program combining progressive resistance training and moderate-intensity aerobic training. Participants will perform three sessions per week, each lasting approximately 45 minutes. Resistance exercises will use body weight and/or light external loads and will follow progressive overload principles. Aerobic exercise intensity will be adjusted using heart-rate feedback. The intervention will be delivered through a certified digital therapeutic platform including instructional videos, wearable inertial sensors, heart-rate monitoring, automated feedback, and remote professional supervision through chat or video call. Training progression will be individualized using adherence data, functional assessments, and monitoring outputs.
Active Comparator: Sarcopenia - Control; Participants with sarcopenia allocated to the control group will receive general physical activity recommendations in line with current WHO guidelines and general nutritional advice. They will not receive the digitally delivered individualized exercise intervention. Participants will undergo the same assessment schedule as the intervention group, including baseline, Week 12, and Week 48 evaluations of muscle strength, physical performance, balance, body composition, QUS-RF-derived muscle parameters, questionnaires, dietary monitoring, and blood biomarkers, according to the study protocol.	Behavioral: General physical activity recommendations; Participants allocated to the control condition will receive general physical activity recommendations in line with current WHO guidelines and general nutritional advice. They will not receive the digitally delivered individualized exercise program, wearable sensor-based monitoring, automated feedback, or remote exercise supervision. This intervention is intended to represent a standard recommendation-based comparator condition against which the digitally delivered home-based exercise intervention will be evaluated.
Experimental: Pre-sarcopenia - Exercise Intervention; Participants at risk of sarcopenia, defined by reduced muscle mass with preserved muscle strength, allocated to the exercise group will receive a 48-week digitally delivered home-based exercise intervention. The program will combine progressive resistance training using body weight and/or light external loads with moderate-intensity aerobic training. Sessions will be performed three times per week for approximately 45 minutes per session. Training will be monitored through a digital platform including wearable inertial sensors, heart-rate monitoring, instructional videos, automated feedback, and remote professional supervision. Participants will also receive general nutritional advice.	Behavioral: Digitally delivered home-based exercise intervention; Digitally delivered, home-based, 48-week exercise program combining progressive resistance training and moderate-intensity aerobic training. Participants will perform three sessions per week, each lasting approximately 45 minutes. Resistance exercises will use body weight and/or light external loads and will follow progressive overload principles. Aerobic exercise intensity will be adjusted using heart-rate feedback. The intervention will be delivered through a certified digital therapeutic platform including instructional videos, wearable inertial sensors, heart-rate monitoring, automated feedback, and remote professional supervision through chat or video call. Training progression will be individualized using adherence data, functional assessments, and monitoring outputs.
Active Comparator: Pre-sarcopenia - Control; Participants at risk of sarcopenia, defined by reduced muscle mass with preserved muscle strength, allocated to the control group will receive general physical activity recommendations in line with current WHO guidelines and general nutritional advice. They will not receive the digitally delivered individualized exercise intervention. Participants will complete the same assessment schedule as the intervention group, including baseline, Week 12, and Week 48 evaluations of muscle strength, physical performance, balance, body composition, QUS-RF-derived muscle parameters, questionnaires, dietary monitoring, and blood biomarkers.	Behavioral: General physical activity recommendations; Participants allocated to the control condition will receive general physical activity recommendations in line with current WHO guidelines and general nutritional advice. They will not receive the digitally delivered individualized exercise program, wearable sensor-based monitoring, automated feedback, or remote exercise supervision. This intervention is intended to represent a standard recommendation-based comparator condition against which the digitally delivered home-based exercise intervention will be evaluated.
No Intervention: Healthy Reference Cohort; Healthy age-, sex-, and physical activity-matched older adults will be included as a non-randomized reference cohort. These participants will not receive the digitally delivered exercise intervention and will not be assigned to the control condition. They will undergo the scheduled study assessments to provide reference values for diagnostic and longitudinal comparisons, including evaluations of body composition, QUS-RF-derived muscle parameters, muscle strength, physical performance, balance, questionnaires, dietary monitoring, and blood biomarkers at the planned study time points.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in 30-second Chair Stand Test performance	Lower-limb muscle function will be assessed using the 30-second Chair Stand Test. Participants will be asked to complete as many sit-to-stand repetitions as possible within 30 seconds using a standardized protocol. The outcome will be expressed as the number of complete repetitions. The primary analysis will evaluate changes from baseline to Week 12 and Week 48 between the exercise intervention and control groups.	Baseline, Week 12, and Week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in handgrip strength	Maximal handgrip strength will be assessed using a handgrip dynamometer according to a standardized protocol. The outcome will be expressed in kilograms or Newtons, according to the device output. Changes from baseline to Week 12 and Week 48 will be compared between groups.	Baseline, Week 12, and Week 48
Change in lower-limb explosive strength	Explosive strength and rapid force production will be assessed during lower-limb contractions using standardized dynamometric procedures. The outcome will quantify the ability to rapidly generate force and will be used to characterize neuromuscular adaptations to the intervention.	Baseline, Week 12, and Week 48
Change in 6-Minute Walk Test distance	Functional walking capacity will be assessed using the 6-Minute Walk Test. Participants will be instructed to walk as far as possible in 6 minutes according to a standardized protocol. The outcome will be expressed as distance walked in meters.	Baseline, Week 12, and Week 48
Change in Mini-Balance Evaluation Systems Test score	Balance performance will be assessed using the Mini-Balance Evaluation Systems Test. The total score ranges from 0 to 28 points, with higher scores indicating better balance performance. Changes from baseline to Week 12 and Week 48 will be evaluated to assess intervention-related effects on balance.	Baseline, Week 12, and Week 48
Change in fat mass assessed by bioelectrical impedance analysis	Baseline, Week 12, and Week 48	Fat mass will be assessed using bioelectrical impedance analysis according to standardized procedures. The outcome will be expressed in percentage. Changes from baseline to Week 12 and Week 48 will be evaluated.
Change in lean mass assessed by bioelectrical impedance analysis	Lean mass will be assessed using bioelectrical impedance analysis according to standardized procedures. The outcome will be expressed in percentage. Changes from baseline to Week 12 and Week 48 will be evaluated.	Baseline, Week 12, and Week 48
Change in skeletal muscle mass index assessed by bioelectrical impedance analysis	Skeletal muscle mass index will be assessed using bioelectrical impedance analysis according to standardized procedures. The outcome will be expressed as kilograms per square meter. Changes from baseline to Week 12 and Week 48 will be evaluated.	Baseline, Week 12, and Week 48
Change in appendicular skeletal muscle mass index assessed by DEXA	Appendicular skeletal muscle mass will be assessed using Dual-Energy X-ray Absorptiometry. The appendicular skeletal muscle mass index will be calculated as appendicular skeletal muscle mass normalized to height squared. Changes from baseline to Week 48 will be evaluated.	Baseline and Week 48
Change in quantitative ultrasound radio-frequency-derived muscle echo-intensity parameters	Quantitative ultrasound radio-frequency analysis will be used to assess muscle quality and microstructure. The primary QUS-RF parameter will be muscle echo-intensity, derived from standardized ultrasound acquisitions of selected lower-limb muscles. The outcome will be expressed in arbitrary units or grayscale units, according to the image analysis output. Changes from baseline to Week 12 and Week 48 will be evaluated and related to functional outcomes.	Baseline, Week 12, and Week 48
Area under the receiver operating characteristic curve of quantitative ultrasound radio-frequency analysis for sarcopenia classification	The diagnostic performance of quantitative ultrasound radio-frequency-derived muscle parameters for classifying sarcopenia status will be evaluated against reference criteria based on muscle mass and muscle strength. Diagnostic accuracy will be expressed as the area under the receiver operating characteristic curve. The area under the receiver operating characteristic curve ranges from 0.5 to 1.0 for a clinically useful classifier, with higher values indicating better diagnostic accuracy.	Baseline
Change in 12-Item Short Form Health Survey Physical Component Summary score	Health-related physical quality of life will be assessed using the 12-Item Short Form Health Survey Physical Component Summary score. The score ranges from 0 to 100, with higher scores indicating better physical health-related quality of life. Changes from baseline to Week 12 and Week 48 will be evaluated between groups.	Baseline, Week 12, and Week 48
Change in 12-Item Short Form Health Survey Mental Component Summary score	Health-related mental quality of life will be assessed using the 12-Item Short Form Health Survey Mental Component Summary score. The score ranges from 0 to 100, with higher scores indicating better mental health-related quality of life. Changes from baseline to Week 12 and Week 48 will be evaluated between groups.	Baseline, Week 12, and Week 48
Change in mood state assessed by the Profile of Mood States	Baseline, Week 12, and Week 48	Mood state will be assessed using the Profile of Mood States questionnaire. The questionnaire will be used to evaluate psychological well-being and mood-related dimensions over the course of the study.
Change in blood biomarkers related to sarcopenia, inflammation, endocrine regulation, and muscle turnover	Blood samples will be collected to assess clinical and molecular biomarkers related to sarcopenia and muscle health. Biomarkers may include inflammatory markers, neuromuscular junction markers, endocrine markers, muscle protein turnover markers, sarcopenia index components, circulating microRNAs, and immune phenotype markers.	Baseline and Week 48

Collaborators and Investigators

• Sponsor: I.R.C.C.S Ospedale Galeazzi-Sant'Ambrogio
• Collaborators: Universita di Verona

Study record dates

Study Major Dates

• Study Start (Actual): June 3, 2026
• Primary Completion (Estimated): June 3, 2027
• Study Completion (Estimated): June 3, 2029

Study Registration Dates

• First Submitted: June 26, 2026
• First Submitted That Met QC Criteria: July 2, 2026
• First Posted (Actual): July 9, 2026

Study Record Updates

• Last Update Posted (Actual): July 9, 2026
• Last Update Submitted That Met QC Criteria: July 2, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Muscular Atrophy; Atrophy; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Sarcopenia
• Other Study ID Numbers: GR-2024-12378411

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No