United Kingdom

Background: • Identifying low muscle strength is a key step in many operational definitions of sarcopenia including the one proposed by the European Working Group on Sarcopenia in Older People-2 (EWGSOP2). • Assessment of grip strength is commonly used to identify people with low muscle strength. • There are a number of sources of variation in the protocols commonly used to assess grip strength including the type of hand-held dynamometer used. • Studies have shown marked variation in the grip strength achieved by individuals when tested using different makes and models of dynamometer. • The implications of these measurement differences for the case-finding of low muscle strength are not fully understood. • We aimed to assess the impact of measurement differences between 4 different types of commonly-used hand-held dynamometers on the case-finding of low muscle strength. Methods: STUDY DESIGN Randomised, repeated measurements cross-over study. STUDY PARTICIPANTS 118 men and women aged 45-74y who had previously taken part in a market research study, resided in London or the South East of England and met eligibility criteria, attended an assessment at a research office in central London between October 2015 and January 2016. MEASUREMENTS Maximum grip strength (kg) (of 2 trials in each hand) was assessed using four different handheld dynamometers (shown in figure A) in a randomly allocated order. ANALYSIS EWGSOP2 recommended cut-points (&lt;27kg for men; &lt;16kg for women) were applied to estimate prevalence of low muscle strength for each device. Agreement between devices was assessed using kappa statistics. Results: • Mean differences in maximum grip strength of between 4 and 5kg were found when comparing the hydraulic/spring-gauge devices with the electronic devices (Lessof et al, Under review). • These differences were reflected in marked variations in prevalence estimates of low muscle strength by dynamometer type (see figure B) with a range of 3% to 22% for men and 3% to 15% for women. • Of the 13 men classified as having low muscle strength by at least 1 dynamometer, only 1 man (8%) was identified by all 4 dynamometers and 7 men (54%) were identified by just 1 dynamometer (see figure C). • Of the 15 women classified as having low muscle strength by at least 1 dynamometer, only 1 woman (7%) was identified by all 4 dynamometers and 10 women (67%) were identified by just 1 dynamometer (see figure C). • This poor agreement between devices was reflected in kappa statistics comparing pairs of devices which ranged from 0.13 to 0.55. Conclusions: • Case-finding of low muscle strength is influenced by the type of hand-held dynamometer used. • It is important to identify the sources of variation in the measurement of grip strength (which include dynamometer type, body position during testing etc.) and consider the implications of these for sarcopenia. • We need to fully standardise the assessment of each of the different components of commonly used operational definitions of sarcopenia. • Where standardisation cannot be achieved, methods to take account of sources of variation in measurement need to be identified. • Options for this may include the development of correction factors and the use of different reference values and cut-points for different measurement devices.

ISTRC 2021 - International Sarcopenia Translational Research Conference

Impact of variation in device used to measure grip strength on the identification of low muscle strength: Findings from a randomised cross-over study

hand-held dynamometers

cut-points

grip strength

sarcopenia

measurement

Welcome to the inaugural International Sarcopenia Translational Research Conference.  “Where Worlds Meet” – the event brings together a broad range of researchers and practitioners in a truly interdisciplinary forum, covering discovery science through to clinical practice.

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Background: • Identifying low muscle strength is a key step in many operational definitions of sarcopenia including the one proposed by the European Working Group on Sarcopenia in Older People-2 (EWGSOP2). • Assessment of grip strength is commonly used to identify people with low muscle strength. • There are a number of sources of variation in the protocols commonly used to assess grip strength including the type of hand-held dynamometer used. • Studies have shown marked variation in the grip strength achieved by individuals when tested using different makes and models of dynamometer. • The implications of these measurement differences for the case-finding of low muscle strength are not fully understood. • We aimed to assess the impact of measurement differences between 4 different types of commonly-used hand-held dynamometers on the case-finding of low muscle strength. Methods: STUDY DESIGN Randomised, repeated measurements cross-over study. STUDY PARTICIPANTS 118 men and women aged 45-74y who had previously taken part in a market research study, resided in London or the South East of England and met eligibility criteria, attended an assessment at a research office in central London between October 2015 and January 2016. MEASUREMENTS Maximum grip strength (kg) (of 2 trials in each hand) was assessed using four different handheld dynamometers (shown in figure A) in a randomly allocated order. ANALYSIS EWGSOP2 recommended cut-points (<27kg for men; <16kg for women) were applied to estimate prevalence of low muscle strength for each device. Agreement between devices was assessed using kappa statistics. Results: • Mean differences in maximum grip strength of between 4 and 5kg were found when comparing the hydraulic/spring-gauge devices with the electronic devices (Lessof et al, Under review). • These differences were reflected in marked variations in prevalence estimates of low muscle strength by dynamometer type (see figure B) with a range of 3% to 22% for men and 3% to 15% for women. • Of the 13 men classified as having low muscle strength by at least 1 dynamometer, only 1 man (8%) was identified by all 4 dynamometers and 7 men (54%) were identified by just 1 dynamometer (see figure C). • Of the 15 women classified as having low muscle strength by at least 1 dynamometer, only 1 woman (7%) was identified by all 4 dynamometers and 10 women (67%) were identified by just 1 dynamometer (see figure C). • This poor agreement between devices was reflected in kappa statistics comparing pairs of devices which ranged from 0.13 to 0.55. Conclusions: • Case-finding of low muscle strength is influenced by the type of hand-held dynamometer used. • It is important to identify the sources of variation in the measurement of grip strength (which include dynamometer type, body position during testing etc.) and consider the implications of these for sarcopenia. • We need to fully standardise the assessment of each of the different components of commonly used operational definitions of sarcopenia. • Where standardisation cannot be achieved, methods to take account of sources of variation in measurement need to be identified. • Options for this may include the development of correction factors and the use of different reference values and cut-points for different measurement devices.

poster

Sarcopenia (‘poverty of flesh’) is the progressive degenerative loss of muscle mass and strength associated with ageing. 1) Sarcopenia is a major component of frailty and a barrier to independent living in old age. 2) The reticulospinal tract (RST) is a key neural structure in the control of balance, posture and strength. These all falter with age, but little is known about reticulospinal changes with ageing. 3) We hypothesised that age-related reductions in strength might relate to differential changes in corticospinal and reticulospinal connectivity. 4) Transcranial Magnetic Stimulation (TMS) can be used to elicit Motor Evoked Potentials (MEPs) to measure spinal pathways. 5) Contralateral and ipsilateral MEPs are carried by mainly corticospinal and reticulospinal pathways respectively.

Ipsilateral Motor Evoked Potentials as a measure of the reticulospinal tract in age-related strength changes

Background - Patients with chronic kidney disease (CKD) => loss of muscle mass (MM) and strength => Quick and easy diagnosis of MM and strength loss (sarcopenia) is warranted • Ultrasound (US) is a recommended tool to monitor muscle health in CKD [1] , however, it is unknown whether total MM can be diagnosed by a single site measurement • When choosing the anatomical site to be measured, an appropriate surrogate marker of appendicular skeletal muscle mass or total MM should be considered.
Results RF-CSA was a significant (p<0.001) predictor of total MM.

Prediction and validation of total muscle mass by a single site ultrasound measurement in chronic kidney disease patients 


Background: Dietary protein supplementation combined with resistance exercise (RE) may counteract declines in muscle strength, mass, and function (sarcopenia), but the role of whole foods rich in protein, such as milk, is less well understood. In the MIlkMAN study, we aimed to examine the feasibility and acceptability of milk+RE as an intervention for muscle function in community-dwelling older adults, and provide exploratory pilot data for future substantive research in population at risk of sarcopenia. Methods: In a parallel groups design, 30 older adults (71.7±3.6 years; 12 women) were randomised into three groups: WM (whole milk 3.6% fat)+RE, SM (skimmed milk 0.3% fat)+RE, and C (isocaloric carbohydrate drink)+RE. RE was performed twice-weekly over 6 weeks in a community gym, followed by the consumption of 500 ml of milk (~20 g protein) or carbohydrate drink immediately after exercise and a further 500 ml at home within the following 4-5 hours. The feasibility and acceptability of the study was determined by calculating recruitment and attendance rates, compliance with the intervention, rating participants' experiences, and recording adverse health events. Results: The response rate was 49% (out of 400 invitations sent), and the recruitment rate was 73.2% (30 participants recruited out of 41 screened for eligibility). Twenty-nine participants completed the intervention-an attendance rate of 97.1%; 89.7% rated their experience as 'excellent'/very good'. Compliance with taking the drinks was 97.1% (WM), 98.3% (SM), and 95.0% (C); 93.1% rated their drink intake as 'easy'/'very easy' with no adverse effects. Collection of exploratory pilot data to inform future trials was successful. Mean change in grip strength, 5-chair rises, and gait speed were 0.9±3.4 kg, 1.8±2.2 s, 0.1±0.1 m/s, respectively with no differences between the groups. Conclusions: This community-based milk+RE intervention was feasible and acceptable to older adults. The study successfully collected pilot data for future substantive research.

Milk Intervention Muscle AgeiNg (MIlkMAN) pilot study: feasibility and acceptability of a milk and resistance exercise intervention in older adults

Introduction: Lower-limb impairment is common after stroke, limiting independence of those affected. Early, accurate prediction of recovery could enable individualised rehabilitation and optimise outcomes. Previous evidence supports an effect of stroke-related damage to corticospinal tracts (CST) on functional recovery. However, effects of post-stroke sarcopenia, resultant muscle fiber-type shift and inflammation are unknown. An algorithm accounting for these changes, based on combined MRI imaging of the source-organ (brain) and end-organ (lower-limb skeletal muscle), may have superior accuracy compared with clinical assessments or isolated MRI biomarkers. We aim to assess the feasibility and utility of MRI biomarkers for predicting lower-limb recovery following stroke. Methods: 30 patients will be recruited from two North-East England NHS trusts within four weeks of their first-ever ischaemic stroke causing unilateral lower-limb weakness. Patients undergo brain and thigh muscle MRI, including volumetric sequences, lipid and oedema-based muscle imaging and diffusion tensor imaging of the CST. This is followed by baseline and 3-month clinical assessments of: lower-limb impairment (Fugl-Meyer; Motor NIHSS) strength (handheld-dynamometry) and function (Functional Ambulatory Category). Results: 10/30 participants have been recruited since 2019 and the study will close in 2021. Correlations between MRI, clinical and 3-month follow-up outcome data will assess relationships between biomarkers and outcomes to inform a predictive model incorporating baseline clinical and MRI data. Conclusion: This project will provide novel data on sarcopenia-based measures in stroke recovery. If our model has predictive value, a sample size estimate will be calculated to inform future multicentre studies with the aim of developing a robust predictive algorithm.

Study in Novel Neuro-muscular Imaging Biomarkers for Motor Outcome in Stroke

Background: •The increasing longevity of the world’s population together with prolonged survival in many chronic diseases means that more people have loss of mobility. •To target mobility loss effectively and thus be able to prevent it, we need valid tools that can detect and measure it in daily life (1). •It is also of vital importance that mobility outcomes are assessed in relation to other ageing syndromes, including sarcopenia and frailty. Digital technology has the potential for measuring and monitoring digital mobility outcomes in the real world, but as yet there are no robust, validated technology solutions. Methods: • The overarching objectives of Mobilise-D (“Connecting digital mobility assessment to clinical outcomes for regulatory and clinical endorsement”) are to: • Deliver a valid solution for real-world digital mobility assessment; • Validate digital mobility outcomes in predicting clinical outcome in a variety of disease states including Parkinson’s disease, chronic obstructive pulmonary disease, multiple sclerosis, and proximal femoral fracture; and • Obtain regulatory and health stakeholder approval for digital mobility assessment. Results: •Mobilise-D is funded by the European Innovative Medicines Initiative 2 Joint Undertaking, & includes 34 international research partners based at leading international universities and some of the world’s largest pharmaceutical and technical companies. •Mobilise-D started on 1 April 2019 and will run for five years. •Real-world walking speed and related outcomes assessed in 5 chronic disease populations to derive a device-agnostic algorithm that can be used to predict medically relevant clinical outcomes (e.g., falls, hospitalizations, disability, death) from mobility assessment •A sub-study on sarcopenia and frailty will be conducted within each cohort. Conclusion: Mobilise-D's results will directly facilitate drug development and establish the roadmap for clinical implementation of new, complementary tools to identify, stratify and monitor disability, thereby enabling widespread, cost-effective access to optimal clinical mobility management through personalised healthcare.

Connecting digital mobility assessment to sarcopenia and frailty: the Mobilise-D study

Introduction: • CT-based body composition can distinguish between lean and fat tissue, in contrast to BMI • Low skeletal muscle index (SMI) and low skeletal muscle radiodensity (SMD) are associated with survival in several cancer types • In renal cell cancer (RCC) evidence is limited and inconsistent. Methods: • Patients diagnosed with RCC from 2008-2012 were included • CT-scans at L3 level were collected to assess skeletal muscle index (SMI), skeletal muscle density (SMD), visceral adipose tissue index (VATI) and subcutaneous adipose tissue (SATI) • Clinical data were retrieved from medical records • Multivariable Cox regression with restricted cubic splines were used for examining body composition and overall survival (OS) and recurrence-free survival (RFS) • Analyses were adjusted for age at diagnosis, smoking, tumor stage, Fuhrman grade (and MSKCC and mGPS for stage IV) and mutually adjusted for other body composition parameters. • Stage I-III and stage IV were analyzed separately and gender-specific results are presented. Results: • 719 stage I-III and 320 stage IV patients were included  • Median follow up was 6.35 years (interquartile range 1.41-8.23). Conclusion: • Higher SMD and higher VATI were marginally associated with better survival in RCC patients and might be useful for better prognostication. • However, the added value to current prognostic scores needs to be investigated. 

Skeletal muscle radiodensity and visceral fat are associated with overall survival in renal cell cancer

Introduction: The relationship between body composition and survival in locally advanced rectal cancer patients is under investigation. Methods: A retrospective study of all patients with clinical stage 2-3 rectal cancer who completed neoadjuvant chemoradiotherapy (nCRT) and surgery between 2010 and 2015 at Western Health was performed. Body composition was measured at the third lumbar vertebrae on pre-neoadjuvant treatment imaging. Skeletal muscle index (SMI), adipose tissue and mean muscle attenuation (Hounsfield units, HU) were measured. Primary outcomes were overall (OS) and diseasefree survival (DFS). Results: There were 139 patients treated for stage 2-3 low rectal cancer over 5 years. There were 32 disease recurrences and 30 deaths. Sarcopenia did not result in worse survival. Visceral obesity was predictive of OS (HR 6.43; 95% CI 1.06- 39.1). Skeletal muscle index (cm2/m2) and mean muscle attenuation (HU) were independently associated with improved OS (HR 0.83; 95% CI 0.71-0.96 and HR 0.88; 95%CI 0.78-0.99 respectively) in a multivariate model. The surface area (cm2) of subcutaneous and visceral adipose tissue was independently predictive of OS (HR 1.18; 95%CI 1.03-1.33 and HR 1.16; 95% CI 1.03-1.31 respectively) and DFS (HR 1.13; 95% CI 1.01-1.28 and HR 1.13; 95% 1.00-1.26 respectively) in a multivariate model. Conclusion: CT derived measures of adiposity, muscle mass and density can predict survival in patients with locally advanced rectal cancer undergoing multimodal curative treatment. International cut points for defining body composition phenotypes need revision and may not be suitable for this population.

The association between body composition and survival in locally advanced rectal cancer: An Australian study

Background: Sarcopenia, or a gradual decrease in muscle mass and function, is an inevitable part of the ageing process. Due to reduced muscle strength and power, sarcopenia is a major cause of physical frailty in the elderly, resulting in mobility problems and a loss of physical function and independence. Despite extensive research, sarcopenia is still not well understood at the molecular level. This work aims to determine the effect of dietary restriction (DR) on sarcopenia, as dietary restriction is known to increase average lifespan in a wide variety of organisms. The nematode Caenorhabditis elegans is often used as an invertebrate model system for sarcopenia. In this study, we used a transgenic strain of C. elegans with one of its main muscle proteins, myosin heavy chain B (unc54), fluorescently labelled with GFP to quantify the rate of muscle loss in C. elegans. Average lifespan and age-dependent motility was also determined at various severity of DR. Collectively, our findings show that DR affects sarcopenia; worms under mild and medium DR display a delayed onset of sarcopenia compared to control and severe DR. Methodology: C. elegans isolates: C. elegans N2 (Bristol) expressing GFP-tagged muscle protein (unc54::GFP) was a generous gift from Dr András Málnási-Csizmadi (Eötvös Loránd University, Budapest, Hungary). DR: Worms were cultured on NGM plates (control) or DR plates and transferred to new plates every other day. All lifespan assays were performed at 20°C. Diets were restricted by diluting the concentration of the E.coli food source and included FUdR to supress reproduction. Peptone was removed from the DR media to prevent bacterial growth on the plates. The number of dead and live worms were counted daily, and worms were considered dead when they no longer responded to a gentle touch with a sterilized wormpick. Motility was assessed by subjecting the worms to gentle stroking with a wormpick and their response to the stimulus was grouped into one of three motility classes. Results: Mild and Medium DR increases the lifespan of C. elegans - Worms under mild and medium DR showed the most significant increase in mean lifespan compared to control (P < 0.001 and P = 0.011, respectively). Severe DR resulted in starvation, causing a reduction in mean lifespan (P = 0.026). These results are in line with previous research, which found that worms subjected to mild DR had a longer lifespan, while worms under severe DR had a shorter lifespan. Age-related decline in motility is slower under mild and medium DR - Age-dependent motility data suggests DR alters the motility of C.elegans. Exit from class I occurs later for mild and medium DR conditions compared to control and severe DR. Similarly, the timing of both entry and exit from class II occurs later for mild and medium DR, compared to control and severe DR. Age-related muscle loss is delayed under mild and medium DR - Age-related decrease in GFP-myosin fluorescence was observed, suggesting pronounced sarcopenia for control and various DR conditions. The onset of sarcopenia, however, was dependent on the growth conditions used. Worms under mild and medium DR displayed a delayed onset of sarcopenia compared to the control and Severe DR group. For example, on day 14 of adulthood, the level of GFP-myosin fluorescence is significantly lower in control and severe DR relative to mild and medium DR. Mild and medium DR improves healthspan in C. elegans - Under mild and medium DR, both lifespan and healthspan was extended with a proportional reduction in gerospan. In contrast, worms under control and severe DR showed decreased healthspan and increased gerospan, consistent with the reduced days spent in motility class I and II. Conclusions: • Mild and medium DR increases lifespan and healthspan in C. elegans compared to control. • DR alters motility properties of C.elegans - mild and medium DR conditions delay transition from fitness class I (highest motility) to class II (reduced motility), compared to control, suggesting a delayed onset of sarcopenia. • Fluorescence data confirm increased muscle density and delayed onset of sarcopenia under mild and medium DR conditions compared to control. • Moderate DR improves healthspan and delays the onset of sarcopenia whereas severe DR reduces healthspan and accelerates sarcopenia.

Effect of Dietary Restriction on Muscle Aging in Caenorhabditis elegans

Background: 6 months Exposure to Cigarette smoke 6 months Exposure to Sham-cigarette smoke 2. CS Group 1. Control Group Sarcopenia is a major comorbidity in patients with chronic obstructive pulmonary disease (COPD)1, which has been associated to decreased physical activity. Cigarette smoke (CS) is the leading cause of COPD promoting peripheral muscle wasting and dysfunction. Anabolic and catabolic processes have been associated to sarcopenia in these patients, however the role of intramuscular extracellular matrix (ECM) has not been investigated2. Fibronectin is a glycoprotein ECM, essential for the adhesion of myoblasts on their ECM niche. Ageing of the skeletal muscle has been linked to decreased expression of intramuscular fibronectin and to reduced sensitivity of its receptor (β1-integrin), impacting on FGF2 essential growth factor for satellite cells3,4,5. COL1A1 is an intramuscular ECM involved in muscle regeneration and upregulated upon anabolic stimuli such as exercise training6. This study aims to investigate alterations in the expression of fibronectin and COL1A1 in response to CS. It is hypothesised CS alters the expression of ECMs in perypheral skeletal muscle. The role of ECM in sarcopenia still needs to be demonstrated. Materials and methods: Guinea pig model of COPD. Guinea pigs (n7-10) were exposed to cigarette smoke (24 h, 5 d/wk) for 6 months. Control animals were exposed to sham-cigarette smoke. Gastrocnemius were collected 24 hs after last treatment. (n=7-10). All experiments were approved by institutional Animal Research Committee at Hospital Clinic (Barcelona, Spain). Total RNA was isolated from skeletal muscle from all groups from the COPD guinea pig model as shown above. Intramuscular ECMs were quantified by real-time PCR in reversed transcribed cDNA. Primers were designed and sequences are shown in Table 1. The mRNA expression was calculated using the 2−△△Ct method and is presented as fold changes relative to GAPDH normalisation. Results: Effect of cigarette smoking in gene expression of fibronectin in skeletal muscle - CS significantly reduced the expression of fibronectin (*p=0.022) in a guinea pig model of COPD compared to the controls exposed to sham CS. Values are presented as mean fold change ± SEM; n=6-10. Effect of cigarette smoking in gene expression of COL1A1 in skeletal muscle - CS significantly reduced the expression of COL1A2 (***p=0.0001) in a guinea pig model of COPD compared to the controls exposed to sham CS. Values are presented as mean fold change ± SEM; n=7-10. Conclusions: • Cigarette smoke treatment decreased the expression of the ECMs fibronectin and collagen A1 in peripheral skeletal muscle of a guinea pig model of COPD. • As fibronectin and COL1A1 are integral components of intramuscular ECM and are involved in muscle structure and myogenesis2, their transcriptional downregulation may impact on the capacity of the skeletal muscle regeneration and maintenance of muscle mass.

Cigarette smoke decreases the expression of fibronectin and COL1A1 in the locomotor muscle of a guinea pig model of COPD

Background: Sarcopenia (loss of muscle mass, strength and function with age) is associated with disability, mortality and significant healthcare costs • Previous studies have examined measures of muscle mass, strength and function in relation to adverse health outcomes • No studies have explored both levels and changes in these measures in relation to multiple health outcomes in a single cohort • We examined this among participants of the Health, Aging and Body Composition (Health ABC) Study. Methods: • Analyses were based on 1412 men and 1490 women (aged 70-79 years at baseline) from the Health ABC Study (USA) • Characteristics ascertained from baseline (Year 1) to Year 6 • Muscle function by gait speed • Muscle strength by grip dynamometry • Appendicular lean mass (ALM) from DXA • Exposures for gait speed, grip strength and ALM • Mean levels over Years 1 to 6 • Change in z-scores (age and sex-specific) from Years 1 to 6 using linear mixed models • Time-to-first-event Cox regression was used to examine exposures in relation to adverse health outcomes. All models accounted for age, sex and ethnicity; fully-adjusted models also accounted for socio-demographic, lifestyle and clinical characteristics. • 10-year follow-up of outcomes after Year 6 • Deaths (adjudicated) • Hospital admissions (self-reported and adjudicated) • Low trauma fractures (self-reported and adjudicated) • Falls (self-reported). Results: • Participant characteristics are presented in Table 1 • Sarcopenia components were greater among men • Deaths and hospital admissions were more common among men • Low trauma fractures and falls were more common among women • Predictors of adverse health outcomes (Figure 1) • Mortality: lower levels and greater declines in each component • Hospital admission: lower levels and greater declines in each component; p=0.06 for ALM level • Low trauma fracture: lower levels of each component and greater declines in gait speed • Falls: lower gait speed and grip strength and greater declines in gait speed and ALM. Conclusion: • Lower levels and greater declines in muscle mass, strength and function predicted adverse outcomes • Lower gait speed and grip strength were more strongly associated with outcomes than lower ALM • Lifecourse interventions to maximise peak levels in earlier life and to reduce declines in later life may reduce disease burden in this age group. 

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Impact of variation in device used to measure grip strength on the identification of low muscle strength: Findings from a randomised cross-over study

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Ipsilateral Motor Evoked Potentials as a measure of the reticulospinal tract in age-related strength changes

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