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Abstract
Introduction Among chronic diseases affecting older adults, metabolic syndrome (MetS) is known to be closely related to sarcopenia. Insulin resistance may play a key role in the increased frequency of sarcopenia associated with metabolic disorders. To date, an exercise–nutrition combined intervention has been the treatment of choice for sarcopenia. However, trials of combined interventions for individuals with sarcopenia and MetS are still lacking. This study aims to develop and conduct a standardised intervention, named the Multidisciplinary combined Exercise and Nutrition inTervention fOR Sarcopenia (MENTORS), for sarcopenic older patients with MetS.
Methods and analysis This multicentre, randomised controlled trial includes 168 community-dwelling older adults with sarcopenia and MetS. The 12-week MENTORS comprises an exercise intervention consisting of an introductory phase (3 weeks; twice-weekly visits), an expanded phase (3 weeks; twice-weekly visits) and a maintenance phase (6 weeks; once-weekly visits); and a nutrition intervention tailored to the nutritional status of individual subjects. Outcomes will be measured at 0-week, 12-week and 24-week postintervention. The data will be analysed using the intention-to-treat and per-protocol principle.
Ethics and dissemination Before screening, all participants will be provided with oral and written information. Ethical approval has already been obtained from all participating hospitals. The study results will be disseminated in peer-reviewed publications and conference presentations.
Trial registration number NCT04948736
- Musculoskeletal disorders
- GERIATRIC MEDICINE
- DIABETES & ENDOCRINOLOGY
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STRENGTHS AND LIMITATIONS OF THIS STUDY
The study is designed (single-blind, randomised, controlled) to provide the highest level of evidence.
Combined exercise and nutritional intervention will be applied to the participants with metabolic syndrome and sarcopenia for 12 weeks.
This study is a standardised multidisciplinary intervention for sarcopenia based on a literature review and expert opinions.
Validated measures for sarcopenia will be used: 5-time chair stand test as well as appendicular skeletal muscle mass, the Short Physical Performance Battery, 6-metre walking speed, handgrip strength and the SARC-F questionnaire will be evaluated.
Due to limited public funding, this study will be limited to a two-arm design focusing on interventions that require a validation, not a four-arm design (exercise-only, nutrition-only, combined intervention and placebo groups).
Introduction
Sarcopenia is a condition in which skeletal muscle mass declines and physical capabilities worsen with age, which increases the risk of senility, disability, falls, fractures and mortality.1 An increasing elderly population is a major public health issue that rapidly increases the costs of medical and long-term care.2 Sarcopenia is also linked to a variety of chronic and geriatric illnesses, such as stress fractures, metabolic diseases, degenerative joint diseases and cancer.3 Among these chronic diseases affecting older adults, metabolic syndrome (MetS) is closely related to sarcopenia. Chronic degenerative/geriatric disease-related sarcopenia has a positive prognosis when the appropriate interventions and management of the underlying disease are implemented.4 Targeted treatment not only improves physical function, but also reduces symptoms of the underlying disease.5
Insulin resistance, which is the main pathogenesis of MetS, worsens as sarcopenia progresses because muscle tissue is the principal site for glucose absorption and storage.6 Furthermore, cytokines generated by muscle tissue, such as myokine, interact with adipokine secreted by adipose tissue and help prevent insulin resistance.7 As a result, sarcopenia is linked to MetS.8 Increased muscle mass is known to enhance insulin sensitivity, whereas sarcopenia induces primary hypertension by stiffening arteries.9 Kim et al evaluated the appendicular skeletal muscle mass (ASM) in 414 older adults (144 in a diabetic group and 270 in the control group) in a study investigating the correlation between diabetes and sarcopenia, and found a high prevalence of sarcopenia in the diabetic group.10
Insulin resistance may play a key role in the increased frequency of sarcopenia associated with metabolic disorders. Sarcopenia increased the incidence of glucose metabolic diseases, such as insulin resistance and elevated glycated haemoglobin, in the US National Health and Nutrition Examination Survey III.11 It has also been noted that, as people age, their body composition changes; decreased muscle and increased fat may be seen. Furthermore, lipid deposition in muscle cells, and/or adipose tissue between muscle tissue, is linked to insulin resistance.3
To date, an exercise–nutrition combined intervention has been the treatment of choice for sarcopenia.12 The majority of exercise–nutrition combined intervention trials found that elderly subjects with sarcopenia exhibited improved muscular function.13 This type of intervention combines nutrition with resistance exercise and protein supplementation, and is the most effective therapeutic strategy for improving muscle mass, muscle strength and physical function in elderly patients with sarcopenia.14 15 Studies using this combined method found it was superior to a single intervention in an elderly group, and in men with sarcopenia.16 17
However, no trials using combined intervention for individuals with both sarcopenia and MetS have been published. Furthermore, evidence supporting an integrated management plan targeting all phases of sarcopenia (ie, the acute, recovery/transition and maintenance phases) is lacking. Therefore, we designed a multidisciplinary programme combining exercise and nutrition for older adults with both sarcopenia and MetS, tailored according to their functional and nutritional status. Multicentre clinical trials are well suited to the investigation and validation of standardised, complex interventions, and can also be used to determine ideal clinical outcome indicators for sarcopenia.
Objectives
To develop the standardised Multidisciplinary combined Exercise and Nutrition inTervention fOR Sarcopenia (MENTORS).
To conduct a multicentre, controlled clinical trial comparing the effectiveness of MENTORS with conventional medical care for sarcopenic older patients with MetS.
To establish a community dissemination strategy and test the feasibility of implementing MENTORS in representative community hospitals and clinics.
Method and analysis
Study design
This is a single-blind, multicentre, randomised controlled trial in five tertiary hospitals with a 24-week follow-up period. The trial was registered prospectively at Clinicaltrials.gov (NCT04948736) prior to participant recruitment. Significant protocol modifications will be communicated to the trial registry. Sarcopenia will be assessed before, and immediately and 12 weeks after, completion of the intervention (24-week total study duration) (figure 1).
Trial flow diagram.
Provisional study schedule
Start of study: January 2022.
Recruitment period: January 2022 to December 2023.
Follow-up period: 24 weeks.
Total duration of the study: 30 months
Estimated end of study (last visit of the last patient): June 2024.
Participants and eligibility criteria
Community-dwelling older adults (aged ≥65 years) with sarcopenia and MetS will be included. The study subjects will be recruited from five hospitals. After confirming eligibility among the subjects who voluntarily consent through the subject recruitment poster in each hospital, the screening step will proceed (see online supplemental material 1). Sarcopenia will be diagnosed according to the criteria proposed by the Asian Working Group for Sarcopenia 2019.1 It can be defined as low ASM (<7.0 kg/m2 for male patients and <5.4 kg/m2 for female patients according to duel-energy X-ray absorptiometry, or ASM <7.0 kg/m2 for male patients and <5.7 kg/m2 for female patients using bioimpedance analysis) with low muscle strength (handgrip strength <28 kg for male patients and <18 kg for female patients) or low physical performance (6-metre walking speed <1 m/s, 5-time chair stand test ≥12 s or Short Physical Performance Battery ≤9 s).1 18 MetS will be defined as the presence of at least three of the following five risk factors19: increased waist circumference (male patients ≥90 cm, female patients ≥85 cm (Asian cut-off points)); elevated blood pressure (BP) (systolic BP ≥0130 mm Hg and/or diastolic BP ≥85 mm Hg, or receiving treatment for hypertension); fasting blood glucose ≥5.6 mmol/L (100 mg/dL) or receiving treatment for elevated glucose; triglycerides ≥1.7 mmol/L (150 mg/dL) or receiving treatment for hypertriglyceridaemia; and increased high-density lipoprotein cholesterol (HDL-C) (male patients <1.0 mmol/L (40 mg/dL), female patients <1.3 mmol/L (50 mg/dL) or receiving treatment for HDL-C).
Supplemental material
Participants will be excluded if any of the following conditions were met: estimated glomerular filtration rate ≤30 mL/min per 1.73 m2; vitamin D intake ≥1000 IU per day; controlled diet for the purpose of disease management; disorder of the central nervous system (such as stroke, Parkinson’s disease or spinal cord injury); cognitive dysfunction (Mini Mental Status Examination score <24); difficulty communicating (due for example to severe hearing loss); musculoskeletal conditions affecting physical function (such as limb amputation); long-term use of corticosteroids due to inflammatory disease; malignancy requiring treatment within the previous 5 years; and other medical conditions requiring active treatment. Subjects who refused to participate in the study will be also excluded.
Randomisation
Participants will be randomly assigned to a control group receiving standard care or the MENTORS experimental group according to a table of random numbers. The probability of being assigned to each group will be 1:1. Because it is impossible to blind the subjects due to the nature of the exercise–nutrition intervention, a single blind trial will be conducted in which only the outcome evaluator was blinded. The trial will be conducted over a 12-week period, and the two groups will be compared before the intervention (baseline), immediately after the intervention (12 weeks) and 12 weeks after the intervention (24 weeks).
Combined exercise and nutritional intervention (MENTORS)
The 12-week exercise intervention will consist of three phases: an introductory phase (3 weeks, twice-weekly visits), an expanded phase (3 weeks, twice-weekly visits) and a maintenance phase (6 weeks, once-weekly visits) (table 1). Each 60-minute session will include stretching, resistance exercise and aerobic exercise. In the introductory phase, conventional resistance training will focus mainly on concentric contractions; thereafter, eccentrically biased strengthening and power exercises were applied. Resistance exercises will focus on the upper extremities (biceps curl, dips, front raise, chest press), lower extremities (lateral leg rotation, leg extension, hip abduction, squat, heel raise) and trunk (back extension, curl up, bridge). In the second stage (expanded phase), the strengthening exercises will consist of task-oriented eccentric exercises. The third stage (maintenance phase) will be conducted over 6 weeks and added power/eccentric exercises. In each subsequent stage, the number of repetitions and sets will be increased by 20%. Participants will be encouraged to perform the exercise programme at home on non-visiting days. To improve exercise compliance, we will provide an exercise diary and encouraged study subjects to keep track of their progress, and contacted the study subjects via video call every week to check compliance.
Exercise intervention part of MENTORS
The nutritional intervention will be tailored to the nutritional status and individual eating patterns of the study subjects. The goal of this food intake strategy will be to allow the subjects to achieve optimal nutrition and high protein intake. After each subject’s nutritional status will be evaluated with the Mini Nutritional Assessment (MNA) and Korean Protein Assessment Tool (KPAT),20 which is composed of food type, serving size and eating frequency questionnaires. After achieving questionnaires, we will record and calculate the daily protein intake of all participants using Microsoft Excel (Redmond, Washington, USA). The daily protein intake goal will be determined: MNA 24–30 (well nourished), 1.2 g/kg/day; MNA 17–23.5 (at risk), 1.5 g/kg/day; or MNA <17 (malnourished), 1.5 g/kg/day. Individual dietary counselling was provided by a clinical nutritionist. For protein consumption, we will provide an individualised, protein-rich diet tailored to the preferences of the participants, and/or a protein powder supplement (PROMAX, Korea Medical Foods, Seoul, South Korea; protein: 24 g, saturated fat: 0.5 g, cholesterol: 35 mg, sodium: 120 mg, total carbohydrate: 3 g, dietary fibre: 0 g, sugars: 2 g per 1 scoop (30 g) serve) corresponding to the subjects’ daily protein intake goals. Dietary compliance and adherence will be monitored using a food diary (figures 2 and 3). As the subjects are patients with MetS, their daily caloric intake has been individually assessed during nutritional counselling, with an aim to increase protein intake and to achieve eucaloric diet while simultaneously reducing carbohydrate consumption.
Nutrition intervention tailored according to nutritional status.
Overall flow chart of the MENTORS programme. MENTORS, Multidisciplinary combined Exercise and Nutrition inTervention fOR Sarcopenia.
The control group will participate in a rehabilitation programme based on general good practice medical care and follow-up. They will be given a brochure about exercise and protein-rich foods at their first visit. Exercises such as walking, exercise training, muscle strengthening and aerobic exercise will be tailored to the subjects’ individual abilities and preferences. Medical management, such as inpatient or outpatient treatment of osteoporosis, will be provided. The control group will be instructed to maintain their usual amount of activity and diet during the 6-month evaluation period. To prevent drop-out and check for medical issues, we will contact the subjects every month.
Outcomes measures
The following outcomes will be measured before and immediately after the 12-week intervention, as well as 12 weeks after its completion, for an overall study period of 24 weeks (table 2).
Overview of the outcome measures and assessment time points
The 5-time chair stand test, conducted immediately after the intervention (12 weeks), are the primary outcome measures. The secondary outcome measures before the intervention (baseline), immediately after the intervention (12 weeks) and 12 weeks after the intervention (24 weeks) are as follows: conventional sarcopenic indices (an ASM assessment using dual-energy X-ray absorptiometry and bio-impedance analysis, the Short Physical Performance Battery, 6-metre walking speed, handgrip strength and the SARC-F Questionnaire); nutritional status assessment (MNA and KPAT); psychiatric assessment (Delirium Rating Scale, Korean Mini Mental Status Examination, 2nd edition (score range: 0–30; lower scores indicate a worse outcome) and Korean version of the Geriatric Depression Scale21 (score range: 0–30; lower scores indicate a worse outcome)); and other comprehensive geriatric assessments (Korean version of the Physical Activity Scale for the Elderly, Standardised Swallowing Assessment, Korean version of the Health Empowerment Scale, Korean Activity Daily Life Questionnaire, Korean Instrumental Activities of Daily Living questionnaire (score range: 0–3; higher scores indicates worse outcomes) and the EuroQol-5D22 (EQ-5D; score range: 0–1; lower scores indicate worse outcomes)).
Data analysis
Data will be collected using a standardised data entry form and entered into the data management system. The intention-to-treat and per-protocol principles will be followed for data analysis. Participants undergoing baseline measurements and the first-week intervention will be included in the intention-to-treat analysis; missing data were handled by using the last recorded observation carried forward and multiple imputation methods. Participant characteristics will be described as means and SDs for continuous data and frequencies and percentages for categorical data. To compare paired data between two different points, we will use repeated-measures analysis of variance and the Friedman test for continuous and non-parametric data, respectively. Statistical significance will be defined as p<0.05. All statistical analyses will be performed using SPSS software (V.19.0 for Windows; IBM, Armonk, New York, USA).
Sample size
Based on a previous study,23 the study power will be set at 90% and alpha was set at 0.05, with p<0.05 indicating statistical significance. Using PASS 2020 statistical software (NCSS Statistical Software, Kaysville, Utah, USA), we will determine that, to measure a difference of 2.5 s on the 5-repetition chair test between groups, 50 participants per group will be required. A total of 168 participants will be recruited based on an estimated 80% compliance and 25% dropout rate for the two groups.
Patient and public involvement
While participants will not be involved in the development of the research question and the selection of outcome measures, their needs and preferences will be considered throughout the process. Feedback to the participants regarding scientific results, will be organised on each study site.
Ethics and dissemination
This study protocol received approval from the institutional review board of Seoul National University Bundang Hospital (B-2010/645-005), SMG-SNU Boramae Medical Center (10-2021-107), Seoul National University Hospital (J-2108-192-1249), Jeju National University Hospital (2022-01-017) and Kyung Hee University Medical Center (2022-02-057). The study will be performed in accordance with the relevant guidelines of the Declaration of Helsinki, 1964, as amended in Tokyo, 1975; Venice, 1983; Hong Kong, 1989; and Somerset West, 1996.24 Written informed consent for all interventions and examinations will be obtained at subject participation. The Ethics Board will be informed of all serious adverse events and any unanticipated adverse effects that occur during the study. The study protocol has been registered at Clinicaltrials.gov and will be updated. Direct access to the source data will be provided for monitoring, audits, Research Ethics Committee (REC)/Institutional Review Board (IRB) review and regulatory authority inspections during and after the study. All patient information will be coded anonymously, with only the study team having access to the original data. The study results will be disseminated in peer-reviewed publications and conference presentations.
Discussion
Complex interactions among inflammation, fat deposition and insulin resistance play a role in the relationship between MetS and sarcopenia.25 Insulin resistance is the main cause of MetS and mediates the association between MetS and sarcopenia.26 Because skeletal muscle is a major site of insulin-induced glucose metabolism, reduced skeletal muscle mass causes insulin resistance. This promotes skeletal muscle protein synthesis by increasing lipolysis, which releases free fatty acids from adipose tissue and inhibits the insulin-like growth factor 1 axis.3
Recently, it was reported that sarcopenia is closely related to MetS, type 2 diabetes mellitus and cardiovascular disease.25 Because MetS causes excessive accumulation of visceral fat, elevated BP, fasting hyperglycaemia and abnormal lipid levels, it can increase the risk of diabetes mellitus, cardiovascular disease and even cancer.27 Sarcopenia is also linked to persistent inflammation, which plays a role in the pathophysiology of MetS. IL-6 is an inflammatory cytokine that is increased in a variety of inflammatory illnesses, and its effects on skeletal muscle have previously been investigated.28
Several studies have reported a positive correlation between MetS and sarcopenia. One meta-analysis of 13 cross-sectional studies including 35 581 non-obese adults reported that the prevalence of MetS in those with sarcopenia was 36.45%.29 A large cross-sectional study including 13 620 subjects found a strong correlation between sarcopenia and the frequency of MetS, with a 56% reduction in the risk of MetS for every 1-quartile increase in the limb skeletal muscle index.8 Lower grip strength, which is one of the main diagnostic tools for sarcopenia, is also closely related to the development of MetS.30
Patients who have both MetS and sarcopenia have a higher risk of many health problems than those who have neither condition.31 Therefore, clinical interventions for MetS and sarcopenia should be applied simultaneously. Higher levels of physical activity have been reported to improve MetS and sarcopenia.32 Regular exercise can increase brown adipose tissue, which regulates myostatin secretion and is involved in the regulation of skeletal muscle mass and function.33 A protein-enriched diet and regular exercise can help prevent MetS-related sarcopenia.
Strengths
To our knowledge, this is the first study investigating an exercise and nutrition interventional programme for older adults with both MetS and sarcopenia. Furthermore, no study has investigated whether such a programme can increase muscle mass, muscle strength and muscle function in the same population. For future studies, we intend to develop a standardised, multidisciplinary interventional programme and conduct multicentre clinical trials to compare its effectiveness with conventional medical care for sarcopenic older patients with MetS. To prevent unnecessary use of resources, we have carefully designed our study to be efficient and effective in its use of resources. For instance, we plan to conduct a two-arm design, which will allow us to focus on a specific intervention and reduce the resources needed for a larger, more complex study. Additionally, we plan to conduct this study based on the literature review and expert opinions, which will reduce the need for additional studies and ensure rigorous validation of our results.
Ethics statements
Patient consent for publication
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors SYL and J-YL drafted the study protocol. SYL, JB, JHC, HCJ, EYK, KK, MK, GYS, CWW and J-YL conceptualised and designed this trial. All authors read and approved the final manuscript.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.