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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| High load exercise type | Experimental | 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 |
|
| Low load exercise type | Experimental | 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 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| High load exercise type | Other | Heavier load, fewer reps |
| |
| 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. |
| 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. |
| 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. |
Inclusion Criteria For all patients
OA patients
Rheumatoid arthritis patients
Sarcopenia patients
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Carel Meskers Prof.Dr. | Contact | +31 020-4440763 | c.meskers@amsterdamumc.nl |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23326214 | Background | 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. | |
| 32765951 | Background |
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| ID | Term |
|---|---|
| D001172 | Arthritis, Rheumatoid |
| D010003 | Osteoarthritis |
| D055948 | Sarcopenia |
| ID | Term |
|---|---|
| D001168 | Arthritis |
| D007592 | Joint Diseases |
| D009140 | Musculoskeletal Diseases |
| D012216 | Rheumatic Diseases |
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two-arm parallel-group exploratory trial including a total of 69 patients
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| Low load exercise type |
| Behavioral |
Lighter load, more reps |
|
| 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 |
| 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. |
| 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. |
| 32074420 | Background | 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. |
| 31034380 | Background | Hunter DJ, Bierma-Zeinstra S. Osteoarthritis. Lancet. 2019 Apr 27;393(10182):1745-1759. doi: 10.1016/S0140-6736(19)30417-9. |
| 30295435 | Background | 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. |
| 25940578 | Background | 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. |
| 23865675 | Background | 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. |
| 30052707 | Background | 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. |
| 7826134 | Background | 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. |
| 27288209 | Background | 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. |
| 30920392 | Background | 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. |
| D003240 |
| Connective Tissue Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D009133 | Muscular Atrophy |
| D020879 | Neuromuscular Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D001284 | Atrophy |
| D020763 | Pathological Conditions, Anatomical |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D012816 | Signs and Symptoms |