This protocol describes a two-arm, parallel-group exploratory trial comparing the effects of strength and endurance exercise on muscle characteristics in patients with rheumatoid arthritis, osteoarthritis, and sarcopenia, hypothesizing that responses are influenced by intramuscular pathology and systemic inflammation.
Key Findings
Background
Muscle weakness is prevalent across rheumatoid arthritis, osteoarthritis, and sarcopenia, and the study posits that responses to exercise are influenced by intramuscular pathology including muscle morphology, mitochondrial function, and systemic inflammation.
The study hypothesizes that 'responses to endurance and strength exercises in patients with muscle weakness are influenced by intramuscular pathology including muscle morphology, mitochondrial function, and systemic inflammation, based on their disease pathology'
Endurance exercises are proposed to improve mitochondrial function and oxidative capacity
Strength exercises are proposed to stimulate myofibrillar protein synthesis
The hypothesis suggests these differences may require 'personalized training schedules'
Methods
The trial will enroll 69 patients across three disease groups randomized to either endurance or strength exercise interventions.
Total sample size is 69 patients: 23 with rheumatoid arthritis (RA), 23 with osteoarthritis (OA), and 23 with sarcopenia (SARC)
Patients are randomized to endurance exercise (n = 35) or muscle strength exercise (n = 34)
Minimization is used to balance disease type and gender across arms
The design is described as a 'two-arm, parallel-group exploratory trial'
Methods
The 8-week exercise intervention includes both supervised and home-based sessions using standardized equipment.
The intervention lasts 8 weeks with two supervised sessions per week
Supervised sessions use a controlled cable pulley device (Reforter™) and fitness equipment
One additional weekly home-based session is included
Total exercise exposure is three sessions per week across both arms
Methods
The primary outcome measure is isokinetic muscle strength assessed via peak torque using the Biodex system.
Peak torque is measured with the Biodex system®
Isokinetic muscle strength was selected as the primary outcome
Muscle endurance is also assessed using the Biodex system as a secondary outcome
The 6 Minute Walk test is included as an additional secondary measure of muscle endurance
Methods
Muscle morphology will be assessed using 3D ultrasound imaging of the vastus lateralis as a secondary outcome.
3D ultrasound imaging is the method specified for muscle morphology assessment
The vastus lateralis is the target muscle for imaging
Muscle morphology is listed among the secondary outcomes alongside mitochondrial function and systemic inflammation
Methods
Mitochondrial function will be analyzed using high-resolution respirometry on muscle biopsies as a secondary outcome.
High-resolution respirometry is the specified analytical method
The analysis requires muscle biopsy samples
Mitochondrial function is positioned as a potential mechanistic variable explaining differential exercise responses between disease groups
Methods
Systemic inflammation will be quantified using multiplex assays or ELISA on serum samples as a secondary outcome.
Both multiplex assays and ELISA are specified as measurement approaches
Serum samples are the biological material used
Systemic inflammation is hypothesized to be a key modulator of exercise response variability across RA, OA, and SARC
Methods
The study is designed as an exploratory trial intended to identify mechanisms of variability in exercise response and provide effect size estimates for future confirmatory studies.
The stated aim is to 'explore differential responses to muscle endurance and muscle strength exercises in patients with RA, OA, and SARC'
Findings are intended to 'identify potential mechanisms underlying variability in exercise response'
The trial will 'provide effect size estimates to guide future confirmatory studies and more targeted exercise interventions'
The trial is registered at ClinicalTrials.gov as NCT06480643 (registered 28-06-24)
What This Means
This paper describes the design and protocol for a clinical trial called the Care for Muscle (C4M) Study, which has not yet reported results. The study is investigating whether different types of exercise — endurance training versus strength training — produce different effects on muscle health in people with three conditions that commonly cause muscle weakness: rheumatoid arthritis, osteoarthritis, and sarcopenia (age-related muscle loss). The researchers plan to enroll 69 participants across these three groups, have them complete an 8-week exercise program with two supervised sessions and one home session per week, and then measure not just how strong their muscles become, but also what happens at the biological level inside the muscles.
This research suggests that the reason some people respond better to one type of exercise than another may be related to what is happening inside their muscle tissue — specifically in how their muscle fibers are structured, how well their mitochondria (the energy-producing parts of cells) function, and how much inflammation is present in their bodies. To investigate this, participants will undergo muscle biopsies, ultrasound imaging, and blood tests before and after the exercise program. The idea is that different diseases cause different kinds of muscle damage at the microscopic level, and those differences might mean that one type of exercise works better than another depending on a person's specific condition.
The practical importance of this study is that it could help explain why exercise programs do not work equally well for everyone and could eventually lead to more personalized exercise prescriptions for people with these chronic conditions. Because this is an exploratory trial, the main goals are to understand the biological mechanisms involved and to collect data that will help design larger, more definitive studies in the future rather than to provide immediate clinical guidelines.
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Sobejana M, Korpershoek R, Steinz M, van der Laken C, van der Leeden M, Jaspers R, et al.. (2026). Effects of exercise on muscle strength and characteristics in rheumatic diseases and sarcopenia: Protocol for the Care for Muscle (C4M) Study.. PloS one. https://doi.org/10.1371/journal.pone.0356181