Effect of Exercise Type on Muscle Quality in Patients With OA, SARC and RA: an Explorative Study (C4M)

Effect of Exercise Type on Muscle Quality in Patients With OA, SARC and RA: an Explorative Study The Care for Muscle Study

C4M hypothesizes that patients with low muscle strength may respond differently to different types of exercise intervention, dependent on the underlying aetiology, i.e. impaired protein synthesis versus metabolic dysfunction and that this response is predictable based on the clinical diagnosis, i.e. rheumatoid arthritis (RA), osteoarthritis (OA) and Sarcopenia alone (SARC) and a number of clinical, blood based and muscle metabolic and architectural biomarkers. Understanding the underlying biochemical response of each patient group to the different type of exercise loading could help with the development of disease-specific training, making it more effective and more predictable on outcomes.

Study Overview

• Status: Not yet recruiting
• Conditions: Osteoarthritis; Rheumatoid Arthritis; Sarcopenia
• Intervention / Treatment: Other: High load exercise type; Behavioral: Low load exercise type

Detailed Description

Rationale: C4M hypothesizes that patients with low muscle strength may respond differently to different types of exercise intervention, dependent on the underlying aetiology, i.e. impaired protein synthesis versus metabolic dysfunction and that this response is predictable based on the clinical diagnosis, i.e. rheumatoid arthritis (RA), osteoarthritis (OA) and Sarcopenia alone (SARC) and a number of clinical, blood based and muscle metabolic and architectural biomarkers. Understanding the underlying biochemical response of each patient group to the different type of exercise loading could help with the development of disease-specific training, making it more effective and more predictable on outcomes.

Objective: to explore effectivity, interaction and predictability of two types of exercise intervention in patients with RA, OA and SARC alone. The primary outcome of this study will be isokinetic muscle strength of the quadriceps in all three target groups.

Study design: two-arm parallel-group exploratory trial including a total of 69 patients: study population 23 patients with OA, 23 patients with RA and 23 patients with SARC alone (according to the revised European Working Group on Sarcopenia in Older People consensus definition (EWGSOP-II criteria, Cruz- Jentoft 2019).

Intervention: Exercise intervention for 3 times a week for 8 weeks.

Main study parameters/endpoints: the main study parameter is the difference in isokinetic muscle strength pre- and post-intervention in all three patient groups. The secondary study parameters include muscle endurance; mitochondrial respiration, gene and protein expression and histology via muscle biopsies; inflammation via bloodwork and feasibility.

Intervention: Exercise intervention for 3 times a week for 8 weeks.

Main study parameters/endpoints: the main study parameter is the difference in isokinetic muscle strength pre- and post-intervention in all three patient groups. The secondary study parameters include muscle endurance; mitochondrial respiration, gene and protein expression and histology via muscle biopsies; inflammation via bloodwork and feasibility.

• Study Type: Interventional
• Enrollment (Estimated): 69
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Carel Meskers Prof.Dr.; Phone Number: +31 020-4440763; Email: c.meskers@amsterdamumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria For all patients

• Low muscle strength defined as hand grip strength (HGS) <27 kg and <16 kg for males and females respectively. If HGS is not possible due to interfering pain or joint- deformity, the chair stand test is used instead, with low muscle strength defined as not able to rise from the chair without arms or a time >15 sec (Cruz Jentoft 2019).
• Gait speed of >0.8m/s to exclude patients who are too disabled to participate in the study (Cruz Jentoft 2019).

OA patients

• Age between 50 and 70
• Patients with either knee and/or hip OA according to clinical American College of Rheumatology (ACR) criteria (Altman 1986).
• Kellgren and Lawrence grading score of 2-4 for hip and/or knee OA (Altman 1991).
• C-reactive Protein (CRP) levels <10mg/L within 3 months prior to enrolment (Sanchez 2014).

Rheumatoid arthritis patients

• Age between 50 and 70
• Diagnosed with RA according to European Alliance of Associations for Rheumatology (EULAR)/ACR criteria (Aletaha 2010).
• Disease activity score in 28 joints (DAS28) 2.8<5.6, as defined by the EULAR criteria (Aletaha 2010), either de novo or despite Disease-Modifying Antirheumatic Drug therapy.
• Stable disease three months prior to the start of the exercise intervention.
• Stable rheumatic medication three months prior to the start of the exercise intervention.
• Stopped the usage of corticosteroids 3 months prior to the start of the exercise intervention.
• Disease duration >1 year and <15 years

Sarcopenia patients

• Age between 50 and 80.
• Sarcopenia without joint involvement (no OA, RA), according to the EWGSOPII criteria (Cruz Jentoft 2019) of low muscle strength defined as HGS <27kg and <16 kg for males and females respectively (dynapenia). This group will therefore primarily involve participants with probable sarcopenia (dynapenia) but may also encompass participants with confirmed sarcopenia (appendicular muscle Lean Mass (ALM)/height2 <7.0 kg/m2 for males and <5.5 kg/m2 for females) as this is not a selection criterion. Severe sarcopenia will be excluded (gait speed <0,8 m/s).
• Exclude patients with joint complaints (RA, OA, or other joint disease).

Exclusion Criteria:

• Body mass index (BMI) < 18 and > 35 Kg/m2
• Contra-indications for exercise testing and prescription as indicated by the ACSM guideline (i.e. progressive increase in heart failure symptoms, myocardial infarction less than three months before the start of the training programme, severe cardiac ischemia upon exertion, respiratory frequency of more than 30 breaths per minute and heart rate at rest >110 beats per minute).
• Participants taking beta-blockers for the duration of the intervention.
• Diagnosed with other neurologic or cachectic diseases or major surgery that may interfere with muscle quality (i.e. multiple sclerosis, ongoing cancer treatment or radiotherapy/ chemotherapy in the previous 6 months).
• Participating in another regular and intense (i.e. high physical loading training such as high-load circuit training for muscle gain and fat loss > 2 times a week) physical training programme within 2 months prior to enrolment.
• Ligament/muscle tear and/or other injuries within 6 months.
• Taking drugs (e.g. performance enhancing drugs) or nutritional supplements (e.g. protein powder) known to increase muscle mass.
• Inability to be scheduled for exercise therapy
• Insufficient comprehension of Dutch language or no informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High load exercise type; The patients will perform 6-8 full-body exercises using a load of 60-75% of their 1RM. The exercises will comprise of both compound (multi-joint movement that works multiple muscle groups at the same time) and isolation (movement that targets a single muscle group and involves the movement of a single joint) exercises. Each training session will be preceded by a 3-5mins warm-up. Total exercise duration will vary between 45-60mins, comprising of 3 sets of 10 repetitions with 1 min periods of recovery. Patients will be required to maintain an intensity of 7-8 on a 10-point physical exertion scale	Other: High load exercise type; Heavier load, fewer reps
Experimental: Low load exercise type; Patients will perform 6-8 full-body exercises with a load of 30-45% of their 1RM. This training session will include both bodyweight and circuit training types. Each training session will be preceded by a 5-10mins warm-up. Total exercise duration will vary between 45-60mins (including the warm-up and cool down), with each exercise comprising of 3 sets of 20 repetitions with 1 min periods of recovery. A 5-min cool-down will follow the final rest period. Patients will be required to maintain an intensity of 7-8 on a 10-point physical exertion scale	Behavioral: Low load exercise type; Lighter load, more reps

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Isokinetic muscle strength in Nm/kg	Maximal net joint moment measurements of muscle strength will be assessed using an isokinetic dynamometer (EnKnee, Enraf-Nonius, Rotterdam, the Netherlands). An initial practice attempt will be used for familiarization. Participants will perform three maximal test repetitions to measure the isokinetic strength of the quadriceps and hamstrings for each knee, at 60°/s. Mean quadriceps and hamstring muscle strength per leg will be calculated (in Nm) and divided by the participant's weight (in kg). Muscle strength data (in Nm/kg) of the index knee (most affected knee) will be used (de Zwart 2022). The 1-RM will be defined as the maximal weight in kg a patient could lift for only one repetition	Measured before and after the 8 week- exercise block.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Muscle endurance in number of repetitions	this will be measured by the knee extension test of both legs using an isokinetic dynamometer (EnKnee, Enraf-Nonius, Rotterdam, the Netherlands). The patients will be asked to perform the knee extension exercise at 30% 1RM until muscular failure. The number of repetitions obtained until muscular failure will be the indication of muscle endurance.	Measured before and after the 8 week- exercise block.
Myogenesis	SETD3; MYOD1; MYOG	Measured before the 8 week- exercise block.
Apoptosis & proteolysis	CASP1; CASP3; MURF1; MAFBX; BCL2; Gene + protein USP19	Measured before the 8 week- exercise block.
Oxidative stress & endogenous antioxidants	3NT, Cys-S-NO, MDA*, NOS, NOX, GTHP, GTHO & SOD2; SOD1; CAT; HMOX1; NQO1; NRF2; GPX1	Measured before the 8 week- exercise block.
Mitochondrial biogenesis & function	PPARGC1A; mitochondrial complex I-V (Ci-Cv); NDUFA1, NDUFA2, SDHA, SHDB, UQCRC1, CYC1, COX4I1, COX5A, ATP5B, ATP5A1, CCO, C15ORF48	Measured before the 8 week- exercise block.
Glucose metabolism	GLUT4; SIRT1; FOXO1; AMPK-P	Measured before the 8 week- exercise block.
General inflammatory markers	CRP, ESR	Measured before and after the 8 week- exercise block.
Cytokines	TNFa; IL1b; IL6; IFNy & myokines	Measured before and after the 8 week- exercise block

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Age in years	Subject characteristic	Measured before 8 week- exercise block.
Gender (male or female)	Subject characteristic	Measured before 8 week- exercise block.
Height in centimetres	Subject characteristic	Measured before and after the 8 week- exercise block.
Weight in kilgorams	Subject characteristic	Measured before and after the 8 week- exercise block.
Co-morbidities	If any is present	Measured before 8 week- exercise block.
Medication	Any current medication use or medication use in the past 3-6 months will be recorded.	Measured before 8 week- exercise block.
Educational level	Highest level of education received	Measured before 8 week- exercise block.
Employment status	Employed or unemployed	Measured before 8 week- exercise block.
Marital status	Single, married, divorce, widow etc.	Measured before 8 week- exercise block.
Smoking use	Smoking yes or no	Measured before 8 week- exercise block.
Smoking frequency per day	If patients smoke, the amount of cigarettes per day	Measured before and after the 8 week- exercise block.
Alcohol frequency	If patients drink, the frequency in a day/week	Measured before and after the 8 week- exercise block.
Alcohol use	Alcohol yes or no	Measured before and after the 8 week- exercise block.
BMI in kg/m^2	Anthropometric	Measured before and after the 8 week- exercise block.
Absolute & relative muscle mass in kilograms	InBody S10, Biospace Co., Ltd, Seoul, South Korea) will be used to measure muscle mass. DSM-BIA has been validated for assessing segmental and whole-body composition against dual energy X-ray absorptiometry (DEXA) (Ling 2011). DSM-BIA will not be performed in patients with 1) electronic internal medical devices or implants such as cardiac pacemakers; 2) plasters or bandages interfering with the placement of the electrodes; 3) amputation.	Measured before and after the 8 week- exercise block.
Short-form mini-nutritional assessment	Anthropometrics	Measured before and after the 8 week- exercise block.
Handgrip strength in kilograms	A hand-held dynamometer (JAMAR, Sammons Preston, Inc., 119 Bolingbrook, IL, USA will be used to measure handgrip strength. Subjects will be in a sitting position with elbows flexed at 90 degrees, shoulders adducted and forearms in a neutral position without support and instructed to squeeze the dynamometer maximally three times for each hand, alternating between the right and the left- hand side. Maximal value will be reported in kg.	Measured before and after the 8 week- exercise block.
Short physical performance battery test (score 0-12)	The total score of the SPPB is the sum of the number of points achieved (range between 0 and 12) in each of the test components. The higher the score, the better the patient's performance. Persons with a score between 4 and 9 have an increased risk of new disabilities and are therefore a suitable target group for interventions to improve functioning. People with a higher score are not yet in the danger zone. People with a lower score already experience many limitations and are therefore more likely to be eligible for interventions to maintain functioning and possibly deal with limitations.	Measured before and after the 8 week- exercise block.
6 minutes walk test in metres	The 6 Minute Walk Test is a sub-maximal exercise test used to assess aerobic capacity and endurance. The distance covered over a time of 6 minutes is used as the outcome by which to compare changes in performance capacity.	Measured before and after the 8 week- exercise block.
FitMáx© survey in score	The FitMáx© is a questionnaire consisting of three single answer questions, about the maximum capacity of walking, climbing stairs and cycling. The questionnaire consists of a scale from 0-13 to rate maximum capacity of walking, a scale from 0-11 for maximum capacity of cycling and for the maximum capacity of stair climbing a scale from 0-10 is used.	Measured before and after the 8 week- exercise block.
Patient-Reported Outcome Measures (PROMs)	PROMIS-CAT short forms will be used to self-report of core symptoms and health-related quality of life according to the Item Response Theory. We will assess the domains pain, fatigue, physical function, social function (Witter 2016)	Measured before and after the 8 week- exercise block.
Muscle volume in m^2	Muscle volume will be measured between the origin and distal end of the muscle belly using manual segmentation of the anatomical cross-sections and interpolation in custom software. Average fascicle length (ℓfasc) and pennation angles (αfasc) will be estimated.	Measured before and after the 8 week- exercise block.
Average fascicle length (ℓfasc)	Muscle volume will be measured between the origin and distal end of the muscle belly using manual segmentation of the anatomical cross-sections and interpolation in custom software. Average fascicle length (ℓfasc) and pennation angles (αfasc) will be estimated.	Measured before and after the 8 week- exercise block.
Pennation angles (αfasc)	Muscle volume will be measured between the origin and distal end of the muscle belly using manual segmentation of the anatomical cross-sections and interpolation in custom software. Average fascicle length (ℓfasc) and pennation angles (αfasc) will be estimated.	Measured before and after the 8 week- exercise block.
Muscle physiological cross-sectional area (PCSA)	PCSA will be calculated by dividing muscle volume by ℓfasc. Muscle volume and PCSA will are prime determinants of maximal muscle power and muscle strength, respectively.	Measured before and after the 8 week- exercise block.

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc

Publications and helpful links

General Publications

• Hunter DJ, Bierma-Zeinstra S. Osteoarthritis. Lancet. 2019 Apr 27;393(10182):1745-1759. doi: 10.1016/S0140-6736(19)30417-9.
• Mayhew AJ, Amog K, Phillips S, Parise G, McNicholas PD, de Souza RJ, Thabane L, Raina P. The prevalence of sarcopenia in community-dwelling older adults, an exploration of differences between studies and within definitions: a systematic review and meta-analyses. Age Ageing. 2019 Jan 1;48(1):48-56. doi: 10.1093/ageing/afy106.
• Dardevet D, Remond D, Peyron MA, Papet I, Savary-Auzeloux I, Mosoni L. Muscle wasting and resistance of muscle anabolism: the "anabolic threshold concept" for adapted nutritional strategies during sarcopenia. ScientificWorldJournal. 2012;2012:269531. doi: 10.1100/2012/269531. Epub 2012 Dec 23.
• Bao W, Sun Y, Zhang T, Zou L, Wu X, Wang D, Chen Z. Exercise Programs for Muscle Mass, Muscle Strength and Physical Performance in Older Adults with Sarcopenia: A Systematic Review and Meta-Analysis. Aging Dis. 2020 Jul 23;11(4):863-873. doi: 10.14336/AD.2019.1012. eCollection 2020 Jul.
• Ganz DA, Latham NK. Prevention of Falls in Community-Dwelling Older Adults. N Engl J Med. 2020 Feb 20;382(8):734-743. doi: 10.1056/NEJMcp1903252. No abstract available.
• Hanaoka BY, Ithurburn MP, Rigsbee CA, Bridges SL Jr, Moellering DR, Gower B, Bamman M. Chronic Inflammation in Rheumatoid Arthritis and Mediators of Skeletal Muscle Pathology and Physical Impairment: A Review. Arthritis Care Res (Hoboken). 2019 Feb;71(2):173-177. doi: 10.1002/acr.23775. Epub 2019 Jan 4.
• van Vilsteren M, Boot CR, Knol DL, van Schaardenburg D, Voskuyl AE, Steenbeek R, Anema JR. Productivity at work and quality of life in patients with rheumatoid arthritis. BMC Musculoskelet Disord. 2015 May 6;16:107. doi: 10.1186/s12891-015-0562-x.
• Chen L, Nelson DR, Zhao Y, Cui Z, Johnston JA. Relationship between muscle mass and muscle strength, and the impact of comorbidities: a population-based, cross-sectional study of older adults in the United States. BMC Geriatr. 2013 Jul 16;13:74. doi: 10.1186/1471-2318-13-74.
• Helliwell PS, Jackson S. Relationship between weakness and muscle wasting in rheumatoid arthritis. Ann Rheum Dis. 1994 Nov;53(11):726-8. doi: 10.1136/ard.53.11.726.
• Lemmey AB, Wilkinson TJ, Clayton RJ, Sheikh F, Whale J, Jones HS, Ahmad YA, Chitale S, Jones JG, Maddison PJ, O'Brien TD. Tight control of disease activity fails to improve body composition or physical function in rheumatoid arthritis patients. Rheumatology (Oxford). 2016 Oct;55(10):1736-45. doi: 10.1093/rheumatology/kew243. Epub 2016 Jun 10.
• Steinz MM, Persson M, Aresh B, Olsson K, Cheng AJ, Ahlstrand E, Lilja M, Lundberg TR, Rullman E, Moller KA, Sandor K, Ajeganova S, Yamada T, Beard N, Karlsson BC, Tavi P, Kenne E, Svensson CI, Rassier DE, Karlsson R, Friedman R, Gustafsson T, Lanner JT. Oxidative hotspots on actin promote skeletal muscle weakness in rheumatoid arthritis. JCI Insight. 2019 Mar 28;5(9):e126347. doi: 10.1172/jci.insight.126347.

Study record dates

Study Major Dates

• Study Start (Estimated): December 1, 2024
• Primary Completion (Estimated): January 31, 2027
• Study Completion (Estimated): October 31, 2027

Study Registration Dates

• First Submitted: June 17, 2024
• First Submitted That Met QC Criteria: June 24, 2024
• First Posted (Actual): June 28, 2024

Study Record Updates

• Last Update Posted (Actual): June 28, 2024
• Last Update Submitted That Met QC Criteria: June 24, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: osteoarthritis; rheumatoid arthritis; strength training; sarcopenia; exercise therapy; muscle endurance; RMD
• Additional Relevant MeSH Terms: Nervous System Diseases; Immune System Diseases; Autoimmune Diseases; Neurologic Manifestations; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Muscular Atrophy; Atrophy; Arthritis; Arthritis, Rheumatoid; Osteoarthritis; Sarcopenia
• Other Study ID Numbers: 86908

Drug and device information, study documents

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