United Kingdom

Background: Sarcopenia is a prevalent condition with aging, and it is related to clinical and functional decline. Previously care setting has shown to play an important role in sarcopenia prevalence, plus in Spain aged population has a high percentage of women. Objective: to analyse the clinical and functional characteristics of community-dwelling and institutionalised older women with or without sarcopenia. Methods: Study design: A multicentre cross-sectional study. Setting: Valencia (Spain), Jan 2019-Feb 2020. Sample: older women (n=197), living in community (48.2%) and in residential facilities (51.8%). Clinical variables: number of medications, visits to doctor, number of hospitalisation stays, falls, Abbreviated Charlson’s Comorbidity Index. Results: Sarcopenic older women living in community took more medication (p=0.021) and presented significant functional decline for Barthel Index and biceps strength (both p= 0.0001) compared to non-sarcopenic women. Institutionalised sarcopenic older women showed higher number of falls (p=0.001), a decline of Barthel Index and biceps strength (both p= 0.0001), and also a significant decline in quadriceps strength (p=0.001) and calf circumference (p=0.004) compared to nonsarcopenic women. Conclusion: Number of medication and number of falls are characteristic of sarcopenic women living in community and institutionalised, respectively. The main functional variables that characterise sarcopenic women, whether they live in the community or institutionalised are Barthel Index and biceps strength. Clinicians may take these findings into consideration in order to identify sarcopenic women depending on their living setting.

ISTRC 2021 - International Sarcopenia Translational Research Conference

Clinical and functional characteristics of sarcopenic vs non sarcopenic older women living in different settings

setting

functionality

older adults

sarcopenia

clinical

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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Access to this event requires a registration. Please email Eleanor Lockhart at sarcconf@ncl.ac.uk if you have any questions regarding your registration. 

poster

Introduction: Sarcopenia is defined as the presence of both decreased muscle mass and reduced muscle function. It is highly prevalent amongst the elderly. Current treatment approaches involve exercise and dietary programmes. The RANK-RANKL pathway, a major regulator of bone mass, is inhibited by endogenous osteoprotegerin (OPG) and therapeutic Denosumab. Hypothesis: RANK-RANKL inhibition exerts beneficial effects on muscle mass or function. Study objectives: To determine the effect of OPG on myogenesis and muscle atrophy/hypertrophy in primary myoblasts in vitro. Results: Cytotoxicity of hOPG on primary mouse myoblasts/tubes - MTT was used to measure the cytotoxicity of hOPG on primary mouse myoblasts/tubes - No significant changes in viability were observed in treated proliferating and differentiating myoblasts (data not included here). - OPG treated to myotubes significantly increased their viability. The effect of hOPG on myotube phenotype - MF20 immuno-histochemical staining was used to investigate myotube phenotype when subject to hOPG treatment. - hOPG significantly increased fusion index when treated to differentiating myoblasts for 5 days, and significantly increased, in a dose dependent manner, all phenotype parameters when treated to myotubes. Conclusions: Summary of findings • hOPG (5-20 ng/ml) is not cytotoxic to myoblasts, differentiating myoblasts and myotubes. • hOPG significantly improves the viability of myotubes • Myotube diameter and fusion index is significantly improved when hOPG 5 ng/ml is treated to differentiating myoblasts • hOPG significantly improves myotube phenotype (dose dependent) when treated at late stages of myogenesis • Inhibition of RANKL may influence muscle.

Can RANKL inhibition ameliorate sarcopenia? An in vitro study.

Background: Periodic paralysis (PP) is a rare genetic muscle disease caused by mutations in skeletal muscle ion channels and characterised by episodic flaccid paralysis in association with high (HyperPP) or low serum potassium. Around age 40 the severity of attacks reduces or attacks may even stop but permanent progressive weakness develops. The reason for this is not known. This phenotype transition coincides with the age at which muscle mass and optimal motor function start to decline in healthy individuals. We sought to determine if the phenotype transition in PP is linked to the normal ageing phenotype transition and to explore the mechanisms involved. Methods: A mouse model of Hyper PP, known as Draggen (I582V in SCN4A), was compared to wild-type littermates across a range of ages (13-104 weeks). These mice have already been shown to have episodic attacks and develop permanent progressive weakness from middle age. Only male mice were used as penetrance is incomplete in females. We adapted the Muscle Velocity Recovery Cycle technique from humans to examine murine muscle excitability in vivo. We then examined changes in potassium-induced weakness or caffeine contracture force with age using ex vivo muscle tension testing. Muscles were further characterised by either western blot, histology, or energy charge measurement. For normally distributed data a student’s t-test (±Welch correction) or One or Two-way ANOVA was performed to determine significance. For data that was not normally distributed, Welch Rank test, Mann Whitney U test or Kruskal Wallis ANOVA was performed. When an ANOVA was significant (P<0.05) post hoc Tukey testing was used. Conclusions: 1. The phenotype transition with age is replicated in a mouse model of PP. 2. Intrinsic muscle ageing protects against potassium-induced weakness in Draggen mice. However, it also appears to accelerate impairment of sarcoplasmic reticulum calcium release, mitochondrial impairment and the development of core-like regions, suggesting acquired RyR1 dysfunction as the potential aetiology. 3. This work provides a first description of mechanisms involved in phenotype transition with age in PP. It also a demonstrates how studying phenotype transition with age in monogenic disease can yield novel insights into both disease physiology and the ageing process itself.

Ageing Contributes to Phenotype Transition in the Draggen Mouse Model of Periodic Paralysis

Background: Late-onset Pompe disease (LOPD) is a rare disorder produced by mutations in the GAA gene characterized by progressive muscle weakness. LOPD muscle biopsies show accumulation of glycogen inside lysosomes along with autophagic vacuoles associated with atrophic muscle fibers. The mechanism leading to muscle fiber atrophy and death are not well known. Methods: We analyzed the expression of several atrogens and their regulatory mechanisms on muscle biopsies (n:7) of LODP patients using RealTime-PCR, WB and IF. We obtained myoblasts from biopsies of LOPD patients and studied their proliferation and differentiation rate. We transfected myoblasts with BNIP3 and studied size of the myotubes. We used non-parametric statistic studies to compare groups. P was considered signigficative if P was lower than 0.05. Conclusion: These findings suggest a cascade with inhibition of the AKT-mTOR pathway, activation of expression of BNIP3 leading to mitochondrial damage, mitophagy, and finally to progressive muscle fiber atrophy. Our results open the door to potential new treatments targeting BNIP3 and reducing its deleterious effects on muscle fiber atrophy in Pompe disease.

BNIP3 is involved in muscle fiber atrophy in Late-Onset Pompe Disease

Why Muscle Ageing? Sarcopenia is the age-associated loss of skeletal muscle strength, mass, and function. Sarcopenia exacts a huge personal, social, and economic toll including the loss of independence, a higher risk of institutionalisation, reduced quality of life, and high public health costs. Current interventions - such as exercise, nutritional supplementation, and HRT - engender blunted and highly variable results, and do not resolve the underlying causes of muscle ageing. As such, and in the face of population ageing, there is great interest in better understanding the underlying mechanisms driving skeletal muscle ageing in the hope of introducing preventative interventions and therapeutics. Why Cellular Senescence? Cells enter a senescent state when exposed to a variety of stressors. This cellular senescence (CS) state is defined by irreversible growth arrest and the secretion of pro-inflammatory cytokines, chemokines, and proteases, which are collectively known as the senescence-associated secretory phenotype (SASP). The SASP is thought to contribute to tissue dysfunction by inducing paracrine CS and inflammation, impairing stem cell function, and altering the composition of the extracellular matrix. Senescent cells (SnCs) amass in different tissues with age and at etiological sites in multiple chronic conditions. Importantly, removal of SnCs has been shown to alleviate several pathologies in mice and humans in the context of ageing and age-related diseases. Despite such advancements, it remains unclear whether CS occurs in skeletal muscle and, if so, what its effects during muscle ageing may be. Aims and methods: Using histological and immunohistochemical staining techniques, I aimed to: • Characterise the senescence signature in mouse muscle in vivo. • Determine the phenotypic consequences of CS in skeletal muscle by eliminating SnCs in mice. • Assess the translational potential of these findings in human muscle. Results: Expression of Senescence Markers in Mouse Muscle Fibres - No single, stand-alone marker can identify a senescent cell. Therefore it is standard in the field to assess the expression of multiple markers simultaneously. Here, I have used immunofluorescence stainings of the senescence markers p16 (A), p21 (B), TAF (C), HMGB1 (D), and Lamin B1 (E) to better characterise the senescence phenotype in young and old myofibres in vivo. The results indicate the development of a senescence phenotype in mouse skeletal muscle with age. Study Design and MorpholoCharacterisation Following Senescent Cell Clearance - (A) Diagram depicting study design and treatment protocol. (B) Representative images portraying haematoxylin and eosin, and masson's trichrome stainings. Blue regions indicate fibrotic areas. (C) Dot plots representing fibre size, and percentage fibrotic area in old vehicle, APtreated and D+Q-treated mice. Results indicate improved muscle morphology with SnC clearance. Heatmap of Correlations between Senescence Markers, Morphology and Inflammatory SASP factors - Relationships of interest have been highlighted with a heavierset border. Dark blue indicates strong positive correlation. Dark red indicates strong negative correlation. Conclusions: • In line with the senescence phenotype, markers of senescence p21, p16, and TAF increase with age, while HMGB1 and Lamin B1 are lost with age in mouse skeletal muscle in vivo. • Pharmacogenetic and pharmacologic removal of senescent cells improves overall muscle morphology, particularly fibre size and fibrosis. This indicates that CS is an important factor in skeletal muscle ageing. • p21 and TAF predict severity of morphological decline and SASP-mediated inflammation observed during mouse muscle ageing. • Consistent with a senescence phenotype p16 is elevated with age in human muscle in vivo. However, HMGB1 and Lamin B1 are relatively unchanged. Partial reproducibility of the senescence signature from mouse to human muscle points to limitations in using model organisms to approximate human expression. • Quantifications of additional senescence markers in human muscle are ongoing. Correlations between expression of human senescence markers and physical function/body composition data are also currently underway.

Investigating the Role of Cellular Senescence in Muscle Ageing

Introduction: Sarcopenia has been defined as a progressive and generalised skeletal muscle disorder that occurs in advanced ageing (1). Sarcopenia is associated with increased mortality, disability, risk of falls and increased cost of care during hospital admissions (1-4). In 2019, European Working Group of Sarcopenia in Older People updated their definition of sarcopenia (EWGSOP2) (5) and placed a greater emphasis on the importance of muscle strength. In the last decade, Ireland has experienced an increase in the number of older adults (>65) and the Central Statistics Office has predicted that, by 2030, one in five Irish people will be over the age of 65 (6). Currently, the prevalence of sarcopenia in older adults in Ireland is not known. In community dwelling older adults, the prevalence of sarcopenia is widely debated, ranging from 0-50% (7). The early identification of sarcopenia in older adults is important for preventing the adverse outcomes associated with the muscle disease. One essential component of the model of care of older adults in Ireland is the day hospital service (8). Those attending a day hospital receive medical care and multidisciplinary intervention, due to a change or decline in their health or function. Methods: A consecutive series of older adults attending the Robert Mayne Day Hospital (RMDH) in St James’s Hospital (SJH) Dublin, Ireland were invited to take part in the study between October 2019 and March 2020. Due to limited resources, not all participants could be prescribed a physical accelerometer. However, every third participant was prescribed a physical accelerometer. All accelerometers were worn on the participant’s non-dominant wrist for a 7-day period. Results: A total of 134 participants were recruited to the study. The participants had a mean age of 81.7 (SD 7.1), with a range from 65-98. Sixty-one percent (N=82) were female. Conclusion: This is the first study to apply the EWGSOP2 criteria to older adults living in the community in an Irish day hospital setting. The findings highlight the feasibility of applying the EWGSOP2 screening process easily and safely in this setting. The method of strength test influenced the prevalence as well as which variables were independently associated with sarcopenia, potentially highlighting different pathophysiological changes between the two types of sarcopenia. To appropriately manage sarcopenia, the assessment of sarcopenia needs be more consistent regarding the use of the EWGSOP2 guidelines, as seen with the assessment of muscle strength in this study. More routine assessment of sarcopenia using the EWGSOP2 criteria and consistent assessment tools, would enable a greater understanding of the factors that influence sarcopenia (i.e. falls or hospitalisation) and changes in sarcopenia after hospitalisation or acute illness.

Prevalence of Sarcopenia and Assocaited Factors in Older Adults Attending a Day Hospital Service in Ireland

Introduction: • Sarcopenia often co-occurs with osteoporosis, however most of the evidence has been derived from cross-sectional studies. • There is very limited evidence on the association of sarcopenia and incident osteoporosis from prospective studies. Methods: • 168,684 participants (48.8% of women) were included in this prospective study. • After a median follow-up of 7.4 years, 6,296 were diagnosed with osteoporosis. • Sarcopenia (both pre-sarcopenia and sarcopenia) and its individual components were defined according to the EWGSOP2 criteria (2019). • Associations with incident osteoporosis were investigated using Cox-proportional hazard models adjusted for potential confounder factors: sociodemographic, lifestyle, health-related factors, and morbidity count. Results: • After adjusting for relevant confounding factors, presarcopenia was associated with 1.3-times higher risk of incident osteoporosis in men but not in women. • Sarcopenia was associated with 1.66-times increased incident osteoporosis risk in women but not in men. • In terms of individual components, low muscle mass followed by slow gait speed were associated with a higher risk of incident osteoporosis in both sexes. Discussion: • Pre-sarcopenic men and sarcopenic women had a higher risk of developing osteoporosis even after adjustment for a large range of potential confounders. • Considering that sarcopenia could be prevented, health interventions to improve physical capability may delay or prevent the onset of osteoporosis.

What is the association between sarcopenia and incident osteoporosis? A prospective study from UK Biobank

Background: Association of dietary intake and serum level of polyunsaturated-fatty-acids (omega-3 PUFA) with physical function and body composition in older adults remained inconclusive. Method: Study subjects were 554 women from the Osteoporosis-Risk-Factor-and-PreventionFracture Prevention-Study, with dietary intake assessed with 3-day food record at baseline. Total omega-3 PUFA and DHA blood concentrations were analysed using a highthroughput proton (1H) NMR spectrometry metabolomics platform at the University of Eastern Finland. Multiple physical function tests and short physical performance battery (SPPB) was calculated at the baseline and 3-year followup. Results: The multivariable adjusted models showed statistically-significant associations for ALA with higher SPPB (β= 0.118, P=0.024), knee-extension-force at baseline (β= 0.075, P=0.037) and lower fat mass (β= - 0.081, P=0.034), as well as longer one-leg-stance (βbaseline= 0.119, βfollw-up=0.090, P<0.023), higher walking speed (βbaseline= 0.113, βfollw-up=0.144, P<0.047), and ability to squat to the ground (βbaseline= 0.110, βfollwup=0.096, P<0.047) at baseline and follow-up. Total omega-3 PUFA was statistically-significantly associated with better SPPB (βbaseline= 0.108, P=0.039), one-leg-stance (βbaseline= 0.102, P=0.041), walking speed (βbaseline= 0.110, βfollw-up=0.128, P<0.028) and ability to squat (βbaseline= 0.110, P=0.028). Associations for dietary EPA and DHA, serum omega-3 PUFA and DHA with physical function and body composition was not significant.

Dietary omega-3 polyunsaturated fatty acid and alpha-linolenic acid are associated with sarcopenia indices in older women 65-72 years.
Masoud Isanejad 1, 2, Toni Rikkonen 3, Behnam Tajik 4, Joonas Sirola

Background: Population of elderly in Indonesia is predicted to increase to 36 million in 2025. Increasing in life expectancy will be followed by health problem, one of which is sarcopenia. Screening and diagnosis are required to identify sarcopenia especially in community, so that early and comprehensive management can be applied for elderly. Method: This study is a cross sectional study in elderly population in Sarirejo village office. Total 29 elderly met inclusion criteria were involved in this study. Mini-Cog assessment was performed to screen cognitive impairment. Furthermore database were collected followed by MNA. Examination of lower extremities muscle mass was performed by dual x-ray absorptiometry (DXA) using General Electric health bone health. Physical performance was examined by time up and go (TUG) test. Data result were analyzed and statistically test using Pearson correlation and Ranged Spearman. Results: 27 (93,1%) women and 2 (6,9%) man involved in this study, with educational level of 10,3% (3 sample) have no education level, 48,3% (14 sample) have elementary level, 13,8% (4 sample) have junior high school level, 27,6% (8 sample) have senior high school level. Total of 93,1% (27 sample) were married, and 6,9% (2 sample ) were unmarried. From 29 sample, they were divided into 3 ranged group of age, according to WHO classification. Variable analysis result of TUG score with ranged group of age showed positive correlation with increasing age, F= 3.277, P=0,005. Correlation between age (in common) and TUG score showed result with increasing age (in common), followed by decreasing physical performance (P=0,009; r=0,477). Correlation between body mass index (BMI) score with DXA score showed result with increasing BMI score, followed by higher DXA score (P=<0,001; r=0,838). BMI was also showed positive correlation with sarcopenia group with P=<0,001. There was no correlation between MNA score with sarcopenia (P=0,419) and TUG test with sarcopenia (P=0,674). Conclusion: There was no correlation between MNA score, physical performance with sarcopenia.

Correlation Between Sarcopenia and Tug, and Sarcopenia With Physical Performance in Elderly Subjects in Sarirejo Village Semarang

Introduction: Coronavirus disease-2019 (COVID-19) is an infectious disease caused by SARS-CoV-2 virus.  The role of skeletal muscle mass in modulating immune response is well documented. Whilst obesity is well-established as a key factor in COVID-19 and outcome, no study has examined the influence of both sarcopenia (low muscle mass) and obesity, termed ‘sarcopenic obesity’ on COVID-19 risk. Using the UK Biobank, we aimed to association between sarcopenic obesity and the risk of COVID-19. Methods: Fully adjusted logistic regression used to analyse associations; covariates included age, ethnicity, socioeconomic status, & comorbidity. Discussion: Sarcopenic obesity significantly increased the likelihood of severe COVID-19 above that of obesity alone (regardless of low muscle mass definition). The mechanisms for this association are complex but could be a result of a reduction in respiratory functioning, immune response, and ability to respond to metabolic stress, Therapeutic approaches targeting both skeletal muscle and adiposity should form a key part in the treatment of COVID-19. 

Sarcopenic obesity and the risk of hospitalisation or death from COVID-19: findings from UK Biobank

Background: The European Working Group on Sarcopenia in Older People definition (EWGSOP2) follows different assessment steps to identify older adults with sarcopenia. Considering that aged population in Spain has a higher percentage of women, the aim of this study was to detect how the EWGSOP2 assessment steps decline in earlier ages in women in order to focus on them when identifying sarcopenia. Methods: Study design: Multicenter cross-sectional study. Participants: 193 older women (mean age: 77.8 +/- 9.1 years), from Valencia (Spain). Assessments and classification: Assessment steps and cut-offs of the EWGSOP2 algorithm (Figure 1). Assessments which showed detection at earlier ages were included for the classification: 1) probable sarcopenia; 2) confirmed sarcopenia; and 3) severe sarcopenia. Age groups: 65-74, 75-84 and ≥85 years old. Statistical analysis: to compare age groups Chisquare test and 1-factor ANOVA, or ANOVA-Welch adjusted by Bonferroni or Games-Howell, respectively. Results: Chair stand shows decline from 65 years old onwards, while ASM, gait speed and SPPB show it from 75 years, all of them with significant differences as aging occurs (p<0.001). On the contrary, ASM Index remains over the cut-off (>5.5 kg/m2) in all age groups. Consequently, participants were classified according to Chair stand, ASM and SPPB, showing that 50% of women aged ≥85 had severe sarcopenia. Conclusion: Chair stand, ASM and SPPB or gait speed seem to be early measurement detectors of sarcopenia for older women. These measurements should be considered in clinical settings in order to apply early intervention. Conclusion: Chair stand, ASM and SPPB or gait speed seem to be early measurement detectors of sarcopenia for older women. These measurements should be considered in clinical settings in order to apply early intervention.

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Can RANKL inhibition ameliorate sarcopenia? An in vitro study.

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