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Key summary points Aim To assess the feasibility of conducting acute sarcopenia research in complex populations of hospitalised older adults. Findings Recruitment rates were higher in elective surgery patients compared to emergency surgery or medical patients. Drop-out rates were not affected by age or frailty of participants. Completion rates of ultrasound quadriceps were higher than other procedures. Message Acute sarcopenia research represents unique challenges but is feasible provided protocol adaptations are incorporated. Assessment of muscle quantity and quality should be included in early-stage clinical research studies to provide mechanistic insights underpinning interventions, especially where physical performance testing may not be possible or reliable., Purpose To assess feasibility of conducting acute sarcopenia research in complex populations of hospitalised older adults. Methods Patients ≥ 70 years old were recruited to three cohorts: elective colorectal surgery, emergency (abdominal) surgery, medical patients with infections. Participants were recruited to the elective cohort in preoperative assessment clinic, and acutely admitted participants from surgical and medical wards at the Queen Elizabeth Hospital Birmingham. Serial measures of muscle quantity (ultrasound quadriceps, bioelectrical impedance analysis), muscle function (hand grip strength, physical performance), and questionnaires (mini-nutritional assessment, physical function) were performed at baseline, within 7 (± 2) days of admission/surgery, and 13 (± 1) weeks post-admission/surgery. Feasibility outcomes were assessed across timepoints including recruitment and drop-out rates, and procedure completion rates. Results Eighty-one participants were recruited (mean age 79, 38.3% females). Recruitment rates were higher in elective (75%, 24/32) compared to emergency surgery (37.2%, 16/43), and medical participants (45.1%, 41/91; p = 0.003). Drop-out rates varied from 8.3 to 19.5% at 7 days, and 12.5–43.9% at 13 weeks. Age and gender did not differ between patients assessed for eligibility, approached, or recruited. Completion rates were highest for ultrasound quadriceps (98.8%, 80/81 across all groups at baseline). Gait speed completion rates were lower in medical (70.7%, 29/41) compared to elective participants (100%, 24/24) at baseline. Conclusion Higher participation refusal and drop-out rates should be expected for research involving recruitment of participants from the acute setting. Assessment of muscle quantity/quality through ultrasound is recommended in early-stage trials in the acute setting, where completion rates of physical performance testing are expected to be lower.

Sarcopenia, a condition of low muscle mass, quality, and strength, is commonly found in patients with cirrhosis and is associated with adverse clinical outcomes including reduction in quality of life, increased mortality, and posttransplant complications. In chronic liver disease (CLD), sarcopenia is most commonly defined through the measurement of the skeletal muscle index of the third lumbar spine. A major contributor to sarcopenia in CLD is the imbalance in muscle protein turnover, which likely occurs due to a decrease in muscle protein synthesis and an elevation in muscle protein breakdown. This imbalance is assumed to arise due to several factors including accelerated starvation, hyperammonemia, amino acid deprivation, chronic inflammation, excessive alcohol intake, and physical inactivity. In particular, hyperammonemia is a key mediator of the liver-gut axis and is known to contribute to mitochondrial dysfunction and an increase in myostatin expression. Currently, the use of nutritional interventions such as late-evening snacks, branched-chain amino acid supplementation, and physical activity have been proposed to help the management and treatment of sarcopenia. However, little evidence exists to comprehensively support their use in clinical settings. Several new pharmacological strategies, including myostatin inhibition and the nutraceutical Urolithin A, have recently been proposed to treat age-related sarcopenia and may also be of use in CLD. This review highlights the potential molecular mechanisms contributing to sarcopenia in CLD alongside a discussion of existing and potential new treatment strategies.

Background To evaluate the acceptability of handgrip strength, gait speed, quadriceps ultrasound, and Bioelectrical Impedance Analysis (BIA) to older adults conducted during and following hospitalisation. Methods Questionnaire-based study conducted upon completion of prospective cohort study, with follow-up in either Queen Elizabeth Hospital Birmingham (QEHB), UK, or participant’s own home following recent admission to QEHB. Outcome measures were acceptability as defined by total multi-domain score for each test (maximum score 35), and by frailty status. Results Forty adults aged 70 years and older admitted for emergency abdominal surgery, elective colorectal surgery, or acute bacterial infections (general medicine) participated. Handgrip strength (median 33, IQR 30–35; p = 0.001), gait speed (median 32, IQR 30–35; p = 0.002), ultrasound quadriceps (median 33, IQR 31–35; p = 0.001), and BIA (median 33.5, IQR 31–35; p = 0.001) were considered highly acceptable. Participants responded positively that they enjoyed participating in these tests, and considered these tests of importance. There was no difference in scores between tests (p = 0.166). Individual total test scores did not differ between patients with and without frailty. Qualitative data are also presented on drivers for research participation. Conclusions Handgrip strength, gait speed, ultrasound quadriceps, and BIA are acceptable tests to older adults during and following hospitalisation. Our results may serve as standards when evaluating acceptability of other tests. Trial registration Prospectively registered February 2019: https://clinicaltrials.gov/ct2/show/NCT03858192

Objective Assimilate evidence for interventions to ameliorate negative changes in physical performance, muscle strength and muscle quantity in hospitalised older adults. Methods We searched for articles using MEDLINE, Embase, CINAHL and Cochrane library using terms for randomised controlled trials, older adults, hospitalisation and change in muscle quantity, strength or physical performance. Two independent reviewers extracted data and assessed risk of bias. We calculated standardised mean differences for changes in muscle function/quantity pre- and post-intervention. Results We identified 9,805 articles; 9,614 were excluded on title/abstract; 147 full texts were excluded. We included 44 studies including 4,522 participants; mean age 79.1. Twenty-seven studies (n = 3,417) involved physical activity interventions; a variety were trialled. Eleven studies involved nutritional interventions (n = 676). One trial involved testosterone (n = 39), two involved Growth Hormone (n = 53), one involved nandrolone (n = 29), and another involved erythropoietin (n = 141). Three studies (n = 206) tested Neuromuscular Electrical Stimulation. Evidence for effectiveness/efficacy was limited. Strongest evidence was for multi-component physical activity interventions. However, all studies exhibited at least some concerns for overall risk of bias, and considering inconsistencies of effect sizes across studies, certainty around true effect sizes is limited. Conclusion There is currently insufficient evidence for effective interventions to ameliorate changes in muscle function/quantity in hospitalised older adults. Multiple interventions have been safely trialled in heterogeneous populations across different settings. Treatment may need to be stratified to individual need. Larger scale studies testing combinations of interventions are warranted. Research aimed at understanding pathophysiology of acute sarcopenia will enable careful risk stratification and targeted interventions.

Protein ingestion is a potent stimulator of skeletal muscle protein synthesis (MPS). However, older adults demonstrate resistance to anabolic stimuli. Some evidence has demonstrated that a larger acute protein dose is required in older compared to younger adults to elicit the same synthetic response, suggesting that older adults should be consuming higher habitual dietary protein to optimise muscle mass. However, limited research has explored dietary habits in different age groups or the relationship between habitual dietary intake and mechanistic physiological parameters associated with muscle mass and function. This work investigated the effect of habitual dietary intake in young (n = 10, 25.9 (3.2y)) and older (n = 16, 70.2 (3.2y)) community-dwelling adults (16:10 male: female) on physiological muscle parameters. Dietary intake was assessed using four-day diet diaries. Post-absorptive MPS and MPS responses to feeding (4.25x basal metabolic rate; 16% protein) were determined in muscle biopsies of the m. vastus lateralis via stable isotope tracer ([1, 2−13C2]-leucine) infusions with mass-spectrometric analyses. Body composition was measured by dual-energy x-ray absorptiometry. Whole body strength was assessed via 1-repetition maximum assessments. No significant differences in habitual dietary intake (protein, fat, carbohydrate and leucine as g.kgWBLM−1.day−1) were observed between age groups. Whole-body lean mass (61.8 ± 9.9 vs. 49.8 ± 11.9 kg, p = 0.01) and knee-extensor strength (87.7 ± 28.3 vs. 56.8 ± 16.4 kg, p = 0.002) were significantly higher in young adults. Habitual protein intake (g.kg−1.day−1) was not associated with whole-body lean mass, upper-leg lean mass, whole-body strength, knee-extensor strength, basal MPS or fed-state MPS across both age groups. These findings suggest that differences in muscle mass and strength parameters between youth and older age are not explained by differences in habitual dietary protein intake. Further research with a larger sample size is needed to fully explore these relationships and inform on interventions to mitigate sarcopenia development.

Background Lower-limb osteoarthritis (OA) causes high levels of pain and disability. Physiotherapists are the primary healthcare provider of non-pharmacological treatments, and incorporate strategies to optimise physical activity (PA) to aid patients with lower-limb OA to moderate their clinical symptoms. However, patients with lower-limb OA have low adherence to PA recommendations both during treatment and after discharge. This study aimed to use knowledge of identified barriers and facilitators to physiotherapy prescribed PA (during treatment and post-discharge) to develop a theoretically informed intervention to optimise adherence to PA for patients with lower-limb OA during treatment and post-discharge. Methods 1) A purposive sample of 13 patients with lower-limb OA participated in semi-structured interviews following physiotherapy treatment. Inductive analysis identified themes/subthemes reflecting barriers and facilitators to physiotherapist prescribed PA, which were organised deductively according to personal factors, treatment and post-discharge phases. 2) Themes/subthemes were mapped onto the theoretical domains framework (TDF). 3) Behaviour change techniques (BCTs) were coded from the key identified domains and a theoretically informed physiotherapy intervention addressing barriers and using facilitators, was developed. Results Themes of patient confidence, mind-set, motivation, OA symptoms and PA experiences were primary personal factors that influenced PA adherence; with the TDF domain ‘Beliefs about capabilities’ most important to target. During treatment, the theme of routine formation was the major driver of personal factors; and primarily influenced by developing a positive physiotherapist-patient relationship. Post-discharge, physical factors, psychosocial factors and ongoing access to resources were important themes influencing PA maintenance. ‘Environmental context and resources’ and ‘social influences’ emerged as the key TDF domains to target during treatment and post-discharge. The proposed theoretically informed intervention included 26 BCTs delivered across conceptual phases of adoption, routine formation, and maintenance. Conclusion A theoretically informed physiotherapy intervention was proposed to optimise PA adherence in patients with lower-limb OA. The included BCTs primarily target patients’ perceived beliefs about their capabilities, by developing a PA routine during treatment and facilitating appropriate psychosocial support and access to resources for PA maintenance post-discharge. The feasibility of delivering the intervention in clinical practice will now be evaluated.

The COVID-19 pandemic has had a devastating global impact, with older adults being most at risk of death from the disease. However, acute sarcopenia occurs in survivors of COVID-19; older adults and the most critically unwell patients are the most at risk. Acute sarcopenia is an under-recognised condition of acute muscle insufficiency, defined by declines in muscle function and/or quantity within six months, usually following a stressor event. This commentary reviews definition and mechanisms of acute sarcopenia in COVID-19 and suggests recommendations for research and clinical practice. Research should now focus on the longer-term consequences of acute sarcopenia in patients who have suffered from COVID-19. At the same time, clinicians need to be increasingly aware of the condition, and measurements of muscle strength, quantity, and physical performance should be embedded into clinical practice. Clinicians should consider the risks of acute sarcopenia when weighing up the risks and benefits of treatment (e.g. dexamethasone), and instigate multidisciplinary treatment including dietetics input.

BackgroundOlder adults are vulnerable to the effects of acute sarcopenia (acute muscle insufficiency) following hospitalisation. However, this condition remains poorly characterised to date. It is hypothesised that acute sarcopenia arises due to a combination of bed rest and inflammatory surge. This study aims to characterise changes in muscle quantity and function, determining which factors (clinical and biological) are most predictive, and how these relate to change in physical function at 13 weeks.MethodsThis study will include three groups of patients aged 70 years and older; patients undergoing elective colorectal surgery, patients admitted for emergency abdominal surgery, and patients admitted under general medicine with acute bacterial infections. Changes in muscle quantity (Bilateral Anterior Thigh Thickness with ultrasound and bioelectrical impedance analysis) and muscle function (muscle strength, physical performance) within 1 week of hospitalisation or surgery will be characterised, with follow-up of patients at 13 weeks. Physical function will be measured using the Patient Reported Outcome Measures Information System, and the Short Physical Performance Battery (or gait speed alone within 1 week of surgery).DiscussionThis study will fully characterise changes in muscle quantity and function in hospitalised older adults and enable risk stratification towards targeted interventions in clinical practice. The results of this study will inform further research involving interventions to ameliorate changes.Trial registrationClinicalTrials.govIdentifier:NCT03858192; Prospectively registered 28th February 2019.

The spread of novel SARS-CoV-2 virus, and the disease COVID-19 that is caused by SARS-CoV-2, continues apace. Saving lives and slowing the worldwide pandemic remain of utmost importance to everyone: the public, healthcare professionals, scientists, industry and governments. It is absolutely essential that advice given to the public is evidence-based, accurate and timely; anything less would mislead and has the potential to cause harm. Popular information channels, such as social media platforms, have been rife with misinformation that has been perpetuated by fear and uncertainty. This has been the case particularly for diet and lifestyle advice. There are recommendations for the prevention of the spread of COVID-19 from the WHO,1 the UK,2 Irish3 and USA4 governments and the European Commission,5 as well as public health and healthcare agencies, including key direction on self-isolation.6 This short original report aims to provide a balanced scientific view on vitamin D and SARS-CoV-2 virus/COVID-19 disease. It provides a succinct summary of the current scientific evidence of associations between vitamin D, influenza, upper respiratory tract infections (URTIs) and immune health. Importantly, the paper concludes with lifestyle strategies for avoiding vitamin D deficiency and ensuring a healthy balanced diet at any time, including during the current pandemic. The overarching messages are as follows: (1) Vitamin D is essential for good health. (2) Many people, particularly those living in northern latitudes (such as the UK, Ireland, Northern Europe, Canada and the northern parts of the USA, northern India and China), have poor vitamin D status, especially in winter or if confined indoors. (3) Low vitamin D status may be exacerbated during this COVID-19 crisis (eg, due to indoor living and hence reduced sun exposure), and anyone who is self-isolating with limited access to sunlight is advised to take a vitamin D supplement according to their government’s recommendations for the general population (ie, 400 IU/day for the UK7 and 600 IU/day for the USA (800 IU for >70 years))8 and the European Union (EU).9 (4) There is no strong scientific evidence to show that very high intakes (ie, mega supplements) of vitamin D will be beneficial in preventing or treating COVID-19. (5) There are evidenced health risks with excessive vitamin D intakes especially for those with other health issues such as a reduced kidney function.

Introduction The extent to which chronic exercise training preserves age-related decrements in physical function, muscle strength, mass and morphology is unclear. Our aim was to conduct a systematic review of the literature to determine to what extent chronically trained master athletes (strength/power and endurance) preserve levels of physical function, muscle strength, muscle mass and morphology in older age, compared with older and younger controls and young trained individuals. Methods The systematic data search included Medline, EMBASE, SPORTDiscus, CINAHL and Web of Science databases. Inclusion criteria i) master athletes mean exercise training duration ≥20 years ii) master athletes mean age of cohort >59 years) iii) at least one measurement of muscle mass/volume/fibre-type morphology and/or strength/physical function. Results Fifty-five eligible studies were identified. Meta-analyses were carried out on maximal aerobic capacity, maximal voluntary contraction and body composition. Master endurance athletes (42.0 ± 6.6 ml kg−1 min−1) exhibited VO2max values comparable with young healthy controls (43.1 ± 6.8 ml kg−1 min−1, P = .84), greater than older controls (27.1 ± 4.3 ml kg−1 min−1, P Conclusion Despite advancing age, this review suggests that chronic exercise training preserves physical function, muscular strength and body fat levels similar to that of young, healthy individuals in an exercise mode-specific manner.

First paragraph: Current demographic trends indicate that by the year 2020, almost one in five of the European population will be aged 65 years or over. Although life expectancy is increasing by 2 years per decade, the period of life spent in good health is not keeping pace and most Europeans spend their last decade in poor health. Consequently, there is an urgent need to understand how lifestyle factors can influence age-related changes from gene to society level and how they may be integrated into a net effect of healthy ageing. It is also crucial to develop and validate interventions and health policies to ensure that more of our older adults have a healthy and active later life. This is an urgent and cross-cutting research priority in Europe, and to achieve this, it is vital to increase research capacity in this area to push forward the frontiers of scientific understanding. The Horizon 2020 funded Marie Curie Sklodowska Innovative Training Network—PANINI is addressing this capacity issue by focusing on research and training in two major interacting lifestyle factors with impact at multiple levels, namely, physical activity and nutrition.

BACKGROUND Sarcopenia is defined as the age-related loss of skeletal muscle mass and function. While all humans lose muscle with age, 2-5% of elderly adults develop functional consequences (disabilities). The aim of this study was to investigate muscle myogenesis in healthy elderly adults, with or without sarcopenia, compared with middle-aged controls using both in vivo and in vitro approaches to explore potential biomarker or causative molecular pathways associated with sarcopenic versus non-sarcopenic skeletal muscle phenotypes during ageing. METHODS Biomarkers of multiple molecular pathways associated with muscle regeneration were analysed using quantitative polymerase chain reaction in quadriceps muscle samples obtained from healthy elderly sarcopenic (HSE, n = 7) or non-sarcopenic (HENS, n = 21) and healthy middle-aged control (HMC, n = 22) groups. An in vitro system of myogenesis (using myoblasts from human donors aged 17-83 years) was used to mimic the environmental challenges of muscle regeneration over time. RESULTS The muscle biopsies showed evidence of satellite cell activation in HENS (Pax3, P

Objectives: Sub-optimal dietary protein consumption may partially underlie the age-related loss of muscle mass and function (sarcopenia). Specifically, dose, timing, source and distribution of dietary protein across the day might influence muscle anabolism in individuals from across the lifespan.Design: The present study aimed to assess daily and meal-specific protein intake, protein source and protein intake pattern in 40 young (23.8 ± 4.3 years), 40 middle-aged (51.6 ± 4.1 years), and 40 old (77.4 ± 7.4 years) individuals using 3-day weighed food diaries.Results: Old individuals consumed on average 83.4 ± 24.6 g of daily protein, which was significantly lower compared with young but not middle-aged individuals who consumed, respectively, 105.1 ± 43.0 g and 97.0 ± 31.1 g of daily protein (P = 0.013). No significant difference in daily protein intake was found with middle-aged individuals. Dietary protein intake pattern was uneven across meals for all groups (P < 0.001 for all). Sources of protein consumption were similar between groups except at lunch where old individuals ingested lower quality proteins compared with middle aged and young individuals.Conclusion: Although total daily protein intake was sufficient in the majority of participants, per-meal protein intake and protein distribution contend the current knowledge regarding optimal protein intakes. Increasing protein intake, especially at breakfast and lunch, could mitigate age-related muscle loss.

IntroductionSarcopenia is a progressive loss in muscle mass, strength and function, the adverse consequences of which are severe, affecting quality of life and placing an increasing burden on social and healthcare systems. Vitamin D status is known to be associated with markers of sarcopenia, namely muscle mass, strength and function. Also, resistance exercise training (RET) is currently the only proven intervention to treat sarcopenia. However, very little data exist on the influence of combining the two interventions of vitamin D supplementation and resistance exercise training, although a recent systematic review provides tentative support for the current study’s hypothesis that the combined intervention may further improve musculoskeletal function above exercise training alone. The aim of the present study is to determine whether vitamin D3supplementation is any more effective in improving musculoskeletal function when combined with RET compared with exercise training alone in older adults.Methods and analysisThis double-blinded randomised placebo-controlled trial will recruit a target of 127 eligible men and women aged ≥65 years living independently or in sheltered housing within the Birmingham area to two groups: (1) 6 months RET and placebo or (2) 6 months RET and 800 IU/d vitamin D3. Measures of muscle power (Nottingham Power Rig), body composition (dual energy X-ray absorptiometry), muscle function (short physical performance battery, timed up and go), falls and fractures as events will be assessed. Assessments will take place at baseline and postintervention, with intermittent monitoring of bone turnover, calcium and vitamin D. The primary outcome will be lower limb extensor power output. Analyses of within-group changes and between-group differences in outcome measures are planned.Ethics and disseminationThe EXVITD study has ethical approval granted by the Black Country National Health Service Research Ethics Committee (14/WM/1220). Results of this trial will be submitted for publication in peer-reviewed journals and presented at conferences. The study is being conducted according to the principles of the Declaration of Helsinki.Trial registration numberNCT02467153; Post-results.

Malnutrition, in particular protein-energy malnutrition, is a highly prevalent condition in older adults, and is associated with low muscle mass and function, and increased prevalence of physical frailty. Malnutrition is often exacerbated in the residential care setting due to factors including lack of dentition and appetite, and increased prevalence of dementia and dysphagia. This review aims to provide an overview of the available literature in older adults in the residential care setting regarding the following: links between sarcopenia, frailty, and malnutrition (in particular, protein-energy malnutrition (PEM)), recognition and diagnosis of malnutrition, factors contributing to PEM, and the effectiveness of different forms of protein supplementation (in particular, oral nutritional supplementation (ONS) and protein-fortified foods (PFF)) to target PEM. This review found a lack of consensus on effective malnutrition diagnostic tools and lack of universal requirement for malnutrition screening in the residential care setting, making identifying and treating malnutrition in this population a challenge. When assessing the use of protein supplementation in the residential care setting, the two primary forms of supplementation were ONS and PFF. There is evidence that ONS and PFF increase protein and energy intakes in residential care setting, yet compliance with supplementation and their impact on functional status is unclear and conflicting. Further research comparing the use of ONS and PFF is needed to fully determine feasibility and efficacy of protein supplementation in the residential care setting.

IntroductionThe improvements in short-term outcome after severe trauma achieved through early resuscitation and acute care can be offset over the following weeks by an acute systemic inflammatory response with immuneparesis leading to infection, multiorgan dysfunction/multiorgan failure (MOF) and death. Serum levels of the androgen precursor dehydroepiandrosterone (DHEA) and its sulfate ester DHEAS, steroids with immune-enhancing activity, are low after traumatic injury at a time when patients are catabolic and immunosuppressed. Addressing this deficit and restoring the DHEA(S) ratio to cortisol may provide a range of physiological benefits, including immune modulatory effects.ObjectiveOur primary objective is to establish a dose suitable for DHEA supplementation in patients after acute trauma to raise circulating DHEA levels to at least 15 nmol/L. Secondary objectives are to assess if DHEA supplementation has any effect on neutrophil function, metabolic and cytokine profiles and which route of administration (oral vs sublingual) is more effective in restoring circulating levels of DHEA, DHEAS and downstream androgens.Methods and analysisA prospective, phase II, single-centre, cross-sectional, randomised study investigating Dehydroepiandrosterone supplementation and its profile in trauma, with a planned recruitment between April 2019 and July 2021, that will investigate DHEA supplementation and its effect on serum DHEA, DHEAS and downstream androgens in trauma. A maximum of 270 patients will receive sublingual or oral DHEA at 50, 100 or 200 mg daily over 3 days. Females aged ≥50 years with neck of femur fracture and male and female major trauma patients, aged 16–50 years with an injury severity score ≥16, will be recruited.Ethics and disseminationThis protocol was approved by the West Midlands – Coventry and Warwickshire Research Ethics Committee (Reference 18/WM/0102) on 8 June 2018. Results will be disseminated via peer-reviewed publications and presented at national and international conferences.Trial registrationThis trial is registered with the European Medicines Agency (EudraCT: 2016-004250-15) and ISRCTN (12961998). It has also been adopted on the National Institute of Health Research portfolio (CPMS ID:38158).Trial progressionThe study recruited its first patient on 2 April 2019 and held its first data monitoring committee on 8 November 2019. DHEA dosing has increased to 100 mg in both male cohorts and remains on 50 mg in across all female groups.

Background Cancer cachexia (cancer-induced muscle wasting) is found in a subgroup of cancer patients leaving the patients with a poor prognosis for survival due to a lower tolerance of the chemotherapeutic drug. The cause of the muscle wasting in these patients is not fully understood, and no predictive biomarker exists to identify these patients early on. Skeletal muscle loss is an inevitable consequence of advancing age. As cancer frequently occurs in old age, identifying and differentiating the molecular mechanisms mediating muscle wasting in cancer cachexia vs. age-related sarcopenia are a challenge. However, the ability to distinguish between them is critical for early intervention, and simple measures of body weight may not be sufficiently sensitive to detect cachexia early. Methods We used a range of omics approaches: (i) undepleted proteome was quantified using advanced high mass accuracy mass spectrometers in SWATH-MS acquisition mode; (ii) phospho epitopes were quantified using protein arrays; and (iii) morphology was assessed using fluorescent microscopy. Results We quantified the soluble proteome of muscle biopsies from cancer cachexia patients and compared them with cohorts of cancer patients and healthy individuals with and without age-related muscle loss (aka age-related sarcopenia). Comparing the proteomes of these cohorts, we quantified changes in muscle contractile myosins and energy metabolism allowing for a clear identification of cachexia patients. In an in vitro time lapse experiment, we mimicked cancer cachexia and identified signal transduction pathways governing cell fusion to play a pivotal role in preventing muscle regeneration. Conclusions The work presented here lays the foundation for further understanding of muscle wasting diseases and holds the promise of overcoming ambiguous weight loss as a measure for defining cachexia to be replaced by a precise protein signature.

The study aim was to comprehensively assess physiological function and muscle morphology in chronically trained older individuals against untrained young and older individuals. In a cross-sectional design, 15 young untrained controls (YC) (20 ± 2.7 years, 78.9 ± 13.3 kg), 12 untrained older controls (OC) (69.8 ± 4.1 years, 77.5 ± 14.2 kg), and 14 endurance-trained master athletes (MA) (67.1 ± 4.1 years, 68.7 ± 6.5 kg) underwent assessments of body composition, aerobic capacity, strength, muscle architecture, and fiber-type morphology. Skeletal muscle index was lower and body fat greater in OC versus MA. Estimated VO2max (mL·kg−1·minute−1) was similar between MA and YC, but lower in OC. Isometric leg strength normalized to fat-free mass was similar between groups, whereas normalized isometric arm strength was greater in YC than MA. Myosin heavy chain (MHC) I fiber area was greater in MA than OC, while MHC II fiber area was greater in YC than OC. MHC II fiber myonuclear domain size was greater in YC than OC and MA, whereas MA had greater MHC I and MHC II fiber capillarization than OC and YC. Satellite cell content was similar between groups. Chronic endurance training enhances indices of muscle morphology and improves body composition and aerobic capacity in older age, with potentially important implications for healthspan extension.

Severe injuries are the major cause of death in those aged under 40, mainly due to road traffic collisions. Endocrine, metabolic and immune pathways respond to limit the tissue damage sustained and initiate wound healing, repair and regeneration mechanisms. However, depending on age and sex, the response to injury and patient prognosis differ significantly. Glucocorticoids are catabolic and immunosuppressive and are produced as part of the stress response to injury leading to an intra-adrenal shift in steroid biosynthesis at the expense of the anabolic and immune enhancing steroid hormone dehydroepiandrosterone (DHEA) and its sulphated metabolite dehydroepiandrosterone sulphate (DHEAS). The balance of these steroids after injury appears to influence outcomes in injured humans, with high cortisol: DHEAS ratio associated with increased morbidity and mortality. Animal models of trauma, sepsis, wound healing, neuroprotection and burns have all shown a reduction in pro-inflammatory cytokines, improved survival and increased resistance to pathological challenges with DHEA supplementation. Human supplementation studies, which have focused on post-menopausal females, older adults, or adrenal insufficiency have shown that restoring the cortisol: DHEAS ratio improves wound healing, mood, bone remodelling and psychological well-being. Currently, there are no DHEA or DHEAS supplementation studies in trauma patients, but we review here the evidence for this potential therapeutic agent in the treatment and rehabilitation of the severely injured patient.

Dynapenia is defined as the age‑related loss of muscle strength, and plays a significant role in the loss of physical function and increased risk of disability among older individuals. The need for an early diagnosis supports the search for a biomarker that reflects muscle ‘weakening’. This has previously proven difficult due to patient heterogeneity at presentation and lack of understanding of the underlying molecular mechanisms. The aim of the present study was to identify potential urinary biomarkers of dynapenia in patients undergoing potentially curative surgery for upper gastrointestinal cancer. Maximum isometric knee extensor strength (strain gauge) and maximum leg extensor power (Nottingham power rig) measurements were taken. Cut‑off values for dynapenia were based on the Allied Dunbar national fitness survey. Values below the 5th percentile for the population matched for age and sex on the Allied Dunbar national fitness survey were used to stratify the cohort into dynapenic or normal. Urine samples taken at induction of anaesthesia were analysed by SELDI‑TOF mass spectrometry using CM10 and IMAC30 chip‑types to establish statistically significant m/z peak fingerprint patterns, followed by in‑gel LC‑MS/MS to identify molecular constituents. Statistical analysis of decision‑tree calculations using Biomarker Pattern software resulted in models with sensitivities of 86 and 96%, specificities of 81 and 89%, and overall correctness of 84 and 93%, when applied to the entire cohort for power and strength measurement‑based stratifications using the IMAC30 chip‑type and the CM10 chip‑type, respectively. The molecular identities of 10 peaks of interest were further investigated. After subtraction of potentially unrelated proteins, they were identified as fragments of Annexin A1, collagen α‑1 (XV), perlecan and myotrophin. These results demonstrate that urinary screening can be used to define cancer‑associated muscle weakness, and the identification of potential biomarkers could be invaluable in establishing a rapid test to measure and assess dynapenia in the clinical setting.

Background Levels of physical activity after stroke are low, despite multiple health benefits. We explored stroke survivors’ perceived barriers, motivators, self-efficacy and intention to physical activity. Methods Fifty independently mobile stroke survivors were recruited prior to hospital discharge. Participants rated nine possible motivators and four possible barriers based on the Mutrie Scale, as having ‘no influence', ‘some influence’ or ‘a major influence’ on physical activity. Participants also rated their self-efficacy and intention to increasing walking. Results The most common motivator was ‘physical activity is good for health’ [34 (68%)]. The most common barrier was ‘feeling too tired’ [24 (48%)]. Intention and self-efficacy were high. Self-efficacy was graded as either 4 or 5 (highly confident) on a five-point scale by [34 (68%)] participants, while 42 (84%) ‘strongly agreed’ or ‘agreed’ that they intended to increase their walking. Conclusion Participants felt capable of increasing physical activity but fatigue was often perceived as a barrier to physical activity. This needs to be considered when encouraging stroke survivors to be more active.

Purpose: Skeletal muscle wasting and weight loss are characteristic features of cancer cachexia and contribute to impaired function, increased morbidity, and poor tolerance of chemotherapy. This study used a novel technique to measure habitual myofibrillar protein synthesis in patients with cancer compared with healthy controls. Experimental design: An oral heavy water (87.5 g deuterium oxide) tracer was administered as a single dose. Serum samples were taken over the subsequent week followed by a quadriceps muscle biopsy. Deuterium enrichment was measured in body water, serum alanine, and alanine in the myofibrillar component of muscle using gas chromatography–pyrolysis–isotope ratio mass spectrometry and the protein synthesis rate calculated from the rate of tracer incorporation. Net change in muscle mass over the preceding 3 months was calculated from serial CT scans and allowed estimation of protein breakdown. Results: Seven healthy volunteers, 6 weight-stable, and 7 weight-losing (≥5% weight loss) patients undergoing surgery for upper gastrointestinal cancer were recruited. Serial CT scans were available in 10 patients, who lost skeletal muscle mass preoperatively at a rate of 5.6%/100 days. Myofibrillar protein fractional synthetic rate was 0.058%, 0.061%, and 0.073%/hour in controls, weight-stable, and weight-losing patients, respectively. Weight-losing patients had higher synthetic rates than controls (P = 0.03). Conclusion: Contrary to previous studies, there was no evidence of suppression of myofibrillar protein synthesis in patients with cancer cachexia. Our finding implies a small increase in muscle breakdown may account for muscle wasting. Clin Cancer Res; 21(7); 1734–40. ©2014 AACR.

Background In order to grow the potential therapeutic armamentarium in the cachexia domain of supportive oncology, there is a pressing need to develop suitable biomarkers and potential drug targets. This pilot study evaluated several potential candidate biomarkers in skeletal muscle biopsies from a cohort of upper gastrointestinal cancer (UGIC) patients. Methods One hundred seven patients (15 weight-stable healthy controls (HC) and 92 UGIC patients) were recruited. Mean (standard deviation) weight-loss of UGIC patients was 8.1 (9.3%). Cachexia was defined as weight-loss ≥5%. Rectus abdominis muscle was obtained at surgery and was analysed by western blotting or quantitative real-time–polymerase chain reaction. Candidate markers were selected according to previous literature and included Akt and phosphorylated Akt (pAkt, n = 52), forkhead box O transcription factors (n = 59), ubiquitin E3 ligases (n = 59, control of muscle anabolism/catabolism), BNIP3 and GABARAPL1 (n = 59, as markers of autophagy), myosin heavy-chain (MyHC, n = 54), dystrophin (n = 39), β-dystroglycan (n = 52), and β-sarcoglycan (n = 52, as markers of structural alteration in a muscle). Patients were followed up for an average of 1255 days (range 581–1955 days) or until death. Patients were grouped accordingly and analysed by (i) all cancer patients vs. HC; (ii) cachectic vs. non-cachectic cancer patients; and (iii) cancer patients surviving ≤1 vs. >1 year post operatively. Results Cancer compared with HC patients had reduced mean (standard deviation) total Akt protein [0.49 (0.31) vs. 0.89 (0.17), P = 0.001], increased ratio of phosphorylated to total Akt [1.33 (1.04) vs. 0.32 (0.21), P = 0.002] and increased expression of GABARAPL1 [1.60 (0.76) vs. 1.10 (0.57), P = 0.024]. β-Dystroglycan levels were higher in cachectic compared with non-cachectic cancer patients [1.01 (0.16) vs. 0.87 (0.20), P = 0.007]. Survival was shortened in patients with low compared with high MyHC levels (median 316 vs. 1326 days, P = 0.023) and dystrophin levels (median 341 vs. 660 days, P = 0.008). Conclusions The present study has identified intramuscular protein level of β-dystroglycan as a potential biomarker of cancer cachexia. Changes in the structural elements of muscle (MyHC or dystrophin) appear to be survival biomarkers.

Although sarcopenic obesity (SO) poses a major public health concern, a robust approach for the optimization of body composition and strength/function in SO has not yet been established. The purpose of this systematic review was to assess the effectiveness of nutritional (focusing on energy and protein modulation) and exercise interventions, either individually or combined, on body composition and strength/function in older adults with SO. MEDLINE, the Cochrane Central Register of Controlled Trials, CINAHL and SPORTDiscus were searched. Main inclusion criteria comprised sarcopenia as defined by the European Working Group on Sarcopenia in Older People (EWGSOP) and obesity defined as % body fat ≥40% (women) and ≥28% (men). Randomized controlled trials (RCTs), randomized controlled crossover trials and controlled clinical trials with older adults (mean age ≥65 years) following a nutritional regimen and/or an exercise training program were considered. Out of 109 full text articles identified, only two RCTs (61 participants) met the inclusion criteria. One study was a nutritional intervention adding 15 g protein·day −1 (via cheese consumption) to the participants' habitual diet. The second study was a high-speed circuit resistance training intervention. Body composition did not change significantly in either of the studies. However, the exercise intervention improved significantly muscle strength and physical function. Although this review was limited by the small number of eligible studies, it provides evidence for the potential benefits of exercise and highlights the necessity for future research to develop effective interventions including dietary and exercise regimens to combat sarcopenic obesity.

After stroke, physical activity and physical fitness levels are low, impacting on health, activity and participation. It is unclear how best to support stroke survivors to increase physical activity. Little is known about the barriers and facilitators to physical activity after stroke. Thus, our aim was to explore stroke survivors' perceived barriers and facilitators to physical activity.Semi-structured interviews with 13 ambulatory stroke survivors exploring perceived barriers and facilitators to physical activity post stroke were conducted in participants' homes, audio-recorded and transcribed verbatim. The Theoretical Domains Framework (TDF) informed content analysis of the interview transcripts.Data saturation was reached after interviews with 13 participants (median age of 76 years (inter-quartile range (IQR) = 69-83 years). The median time since stroke was 345 d (IQR = 316-366 d). The most commonly reported TDF domains were "beliefs about capabilities", "environmental context and resources" and "social influence". The most commonly reported perceived motivators were: social interaction, beliefs of benefits of exercise, high self-efficacy and the necessity of routine behaviours. The most commonly reported perceived barriers were: lack of professional support on discharge from hospital and follow-up, transport issues to structured classes/interventions, lack of control and negative affect.Stroke survivors perceive several different barriers and facilitators to physical activity. Stroke services need to address barriers to physical activity and to build on facilitators to promote physical activity after stroke.Physical activity post stroke can improve physical fitness and function, yet physical activity remains low among stroke survivors. Understanding stroke survivors' perceived barriers and facilitators to physical activity is essential to develop targeted interventions to increase physical activity. Beliefs about capabilities, environmental context and resources and social influences were the mostly commonly report influences on stroke survivors' perceived barriers and facilitators to physical activity.

The purpose of this review was to determine whether very elderly muscle (>75 years) hypertrophies in response to physical training. The databases MEDLINE; EMBASE; CINAHL Plus and SPORTDiscus were systematically literature searched with reference lists of all included studies and relevant reviews. Controlled trials (inactive elderly control group) involving healthy elderly participants over 75 years participating in an intervention complying with an established definition of physical training were included. Data extraction and quality assessment were performed using the PEDro scale. Data analysis was performed on muscle size and strength using RevMan (software version 5.1). Four studies were included of which four of four measured changes in gross muscle size. Training induced increases in muscle size from 1.5%-15.6% were reported in three of four studies, and one of four studies reported a decrease in muscle size (3%). The greatest gain in muscle mass was observed in a study of whole body vibration training. Meta-analysis of three studies found an increase of thigh muscle cross-sectional area (mean difference 2.31 cm(2) or 0.2%, 95% confidence interval (CI): 0.62 to 4.00; P = 0.008) and muscle strength (standardized mean difference 1.04, 95% CI: 0.65 to 1.43; P < 0.001). Physical training when delivered as resistance training has the ability to elicit hypertrophy and increase muscle strength in very elderly muscle.

Summary Sarcopenia is defined as a decline in muscle mass and/or function, which is a consequence of ageing. The consequences of a declining muscle mass become serious if functionally important thresholds for physical independence are crossed, and this will occur more readily in the presence of disease. Although sarcopenia is of complex aetiology, contributory factors likely include habitual sedentarism and/or deficits in the responsiveness of muscle protein synthesis to physical activity and nutrition, as well as impaired muscular regenerative capacity. Altered inflammatory, immune and endocrine functions are also associated with sarcopenia, in addition to phenomena such as a reduced response to oxidative stress, metabolic acidosis and nutritional (e.g. vitamin D) deficiencies. Sarcopenia is associated with malnutrition, which may contribute to the poor muscle function observed in many older adults, particularly in frail patient groups. The problem is that as a result of anabolic resistance, simply increasing dietary protein ‘chronically’ in older age may not be effective. When exercise and nutritional interventions are combined in the form of resistance exercise training plus protein/essential amino acid supplementation, there is evidence of some benefit for older adults in terms of improved muscle function, but further research is needed in adults aged over 75 years. In addition, there are as yet relatively under-researched intervention strategies (timing and distribution of protein supplementation; novel nutriceuticals, vitamin D) bearing potential utility in improving responsiveness to physical activity and nutrition in old age.

Background: Fatigue is a common and distressing consequence of stroke, and the aetiology of post-stroke fatigue (PSF) is poorly understood. It is unclear whether chronic brain changes [cerebral atrophy and white matter lesions (WML)], stroke lesion location or certain clinical features are related to its development. The aim of this study was to identify, in patients with acute stroke, whether features in different brain regions on routine CT imaging or routinely collected clinical features predicted PSF at 1 month. Methods: In total, 107 patients (62% male) with acute ischaemic or haemorrhagic stroke were assessed for fatigue (Fatigue Assessment Scale), anxiety and depression (Hospital Anxiety and Depression Scale) at 1 month. Admission brain CT was rated using a structured scoring system for (i) severity of atrophy and (ii) severity of WML in different regions of the brain, and (iii) site of acute and previous vascular lesions. Results: Cerebral atrophy of mild or greater severity was present in 84 patients (77.5%) and WML of mild or greater severity was present in 54 patients (50.5%) in at least one of the evaluated brain regions. There was no association between PSF and severity of atrophy or WML, or presence of acute or previous vascular lesions. We used the Oxfordshire Community Stroke Project (OCSP) classification to explore the possible influence of lesion location because a minority of the patients (37.4%) had visible acute lesions. Fatigue scores were higher in patients with clinically diagnosed posterior strokes (p = 0.046), in females (p = 0.05) and in those with higher depression and anxiety scores (ρ = 0.52; p < 0.001 and ρ = 0.49; p < 0.001, respectively). Structural CT variables were not significant predictors of fatigue (log FAS) in a linear regression which controlled for age, sex, pre-stroke fatigue, OCSP classification, depression and anxiety. The significant predictors of fatigue were depression (β = 0.30; p = 0.007) and anxiety (β = 0.28; p = 0.013; adjusted R2 = 0.254). Stroke subtype (according to the OCSP classification) was marginally predictive (β = 0.17; p = 0.05) and sex was not statistically significant (β = 0.15; p = 0.08). Conclusions: Features on routine post-stroke CT do not appear to associate with fatigue at 1 month. However, clinically diagnosed posterior strokes as well as female gender, anxiety and depression may be linked with fatigue. Therefore, clinical vigilance rather than CT features should be used to predict fatigue early after stroke. Further research is needed in this area to establish whether biological mechanisms underlie the development of PSF.

Frailty is a common condition affecting older adults, but is not an inevitable part of the ageing process. Frailty is a method of describing the observed heterogeneity in function, disability and health among older people. Importantly what frailty identification allows is the prediction of risk of adverse events such as mortality or disability. Frailty is defined as a syndrome with multiple causes and contributors that is characterised by diminished strength, endurance and reduced physiological function that increases an individual’s vulnerability for developing increased dependency and/or death. Frailty is important clinically as older people with frailty present to healthcare services atypically with frailty syndromes such as falls and delirium. Frail older adults may benefit from assessment by specialist geriatricians and a wider multi-disciplinary team.

OBJECTIVES: The primary aims of this updated review (1) were to determine whether physical fitness training after stroke reduces death, dependence, and disability. The secondary aims were to assess the effects of training on adverse events, risk factors, physical fitness, mobility, physical function, quality of life, mood, and cognitive function. Cognition outcomes have become an important post-stroke intervention target and are therefore added to this review update.

Objective Fatigue is often distressing for stroke survivors. The time course of clinically significant fatigue in the first year after stroke is uncertain. We aimed to determine the frequency, severity and time course of clinically significant fatigue in the first 12 months after stroke onset. Methods We recruited patients with a recent acute stroke. At about one month, six months and 12 months, we performed a structured interview to identify clinically significant fatigue (case definition), and assessed fatigue severity (Fatigue Assessment Scale (FAS)). Results Of 157 patients who initially consented, 136 attended at least one assessment. At one month, 43/132 (33%) had clinically significant fatigue. Eighty-six attended all three assessments, of whom clinically significant fatigue was present in 24 (28%) at one month, 20 (23%) at six months and 18 (21%) at 12 months; their median (IQR) FAS scores were 23 (18 to 29), 21 (17 to 25) and 22.5 (17 to 28) at one, six and 12 months respectively. Of 101 patients who attended at least the one and six month assessments, fatigue status did not change in 65 (64%), with 9 (9%) fatigued throughout and 56 (55%) non-fatigued throughout; 15 (15%) became non-fatigued, 9 (9%) became fatigued, and in 12 (12%) fatigue status fluctuated across three assessments. Conclusion Clinically significant fatigue affected a third of patients one month after stroke. About two thirds of these patients had become non-fatigued by six months, most of whom remained non-fatigued at 12 months. Fatigue persists in a third at 12 months.

Muscle wasting in old age or cancer may result from failed myofiber regeneration and/or accelerated atrophy. This study aimed to determine from transcriptomic analysis of human muscle the integrity of the cellular stress response system in relation to satellite cell differentiation or apoptosis in patients with cancer (weight-stable (CWS) or weight-losing (CWL)) or healthy elderly (HE) when compared with healthy middle-aged controls (HMA). 28 patients with cancer (CWS: 18 and CWL: 10), HE: 21 and HMA: 20 underwent biopsy of quadriceps muscle. The expression of transcription factors for muscle regeneration (Pax3, Pax7 and MyoD) was increased in CWS and HE compared with HMA (p≤0.001). In contrast, the expression of the late myogenic differentiation marker MyoG was reduced in CWS and CWL but increased in HE (p≤0.0001). Bax was significantly increased in CWS, CWL and HE (p≤0.0001). Expression of the oxidative defense genes SOD2, GCLM, and Nrf2 was decreased in CWS and CWL but increased in HE (p≤0.0001). There is evidence for blockade of satellite cell maturation, upregulation of apoptosis and reduced oxidative defense in the muscle of cancer patients. In the healthy elderly the potential for differentiation and oxidative defense is maintained.

Background and purpose Physical fitness is impaired after stroke, may contribute to disability, yet is amenable to improvement through regular physical activity. To facilitate uptake and maintenance of physical activity, it is essential to understand stroke survivors' perceived barriers and motivators. Therefore, we undertook a systematic review of perceived barriers and motivators to physical activity after stroke. Methods Electronic searches of EMBASE, Medline, CINAHL, and PsychInfo were performed. We included peer-reviewed journal articles, in English, between 1 January 1966 and 30 August 2010 reporting stroke survivors' perceived barriers and motivators to physical activity. Results Searches identified 73 807 citations of which 57 full articles were retrieved. Six articles were included, providing data on 174 stroke survivors (range 10 to 83 per article). Two reported barriers and motivators, two reported only motivators, and two reported only barriers. Five were qualitative articles and one was quantitative. The most commonly reported barriers were lack of motivation, environmental factors (e.g. transport), health concerns, and stroke impairments. The most commonly reported motivators were social support and the need to be able to perform daily tasks. Conclusion This review has furthered our understanding of the perceived barriers and motivators to physical activity after a stroke. This review will enable the development of tailored interventions to target barriers, while building upon perceived motivators to increase and maintain stroke survivors' physical activity.

Context In surgical and clinical oncology, there is a growing need for patient-centered outcomes that are responsive, meaningful, and fit for purpose. Objectives The aim of this study was to validate physical activity (PA) monitoring as a responsive outcome measure at different stages of disease and treatment, by verifying correlations between PA, performance score, and quality of life (QoL). Methods Daily life PA of 162 cancer patients, monitored by a device that records time sitting/lying, time standing, time walking, number of steps taken, and walking cadence, was compared with 20 healthy volunteers. In a subgroup of patients, functional status and QoL were assessed using the World Health Organization/Eastern Cooperative Oncology Group and the Karnofsky Performance Status scores and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) questionnaire. Results The PA of patients with resectable gastrointestinal cancer did not differ significantly from controls. In contrast, patients with advanced cancer took 45% fewer steps and spent an extra 2.8 hours/day lying/sitting (P=0.001). Patients undergoing neoadjuvant chemotherapy and surgery (5–6 weeks after operation) experienced a similar reduction in PA. There were significant correlations between PA and the physical and role domains as well as fatigue subscale of the EORTC QLQ-C30 scale. Conclusion Objective PA scores correlate significantly with disease stage, functional status, and QoL of patients with cancer. Therefore, activity monitoring can make meaningful objective estimates of patient function in response to cancer and its treatment and may provide surrogate outcomes of QoL.

Sarcopenia and cachexia are characterized by infiltration of non-contractile tissue within muscle which influences area and volume measurements. We applied a statistical clustering (k-means) technique to magnetic resonance (MR) images of the quadriceps of young and elderly healthy women and women with cancer to objectively separate the contractile and non-contractile tissue compartments.MR scans of the thigh were obtained for 34 women (n = 16 young, (median) age 26 y; n = 9 older, age 80 y; n = 9 upper gastrointestinal cancer patients, age 65 y). Segmented regions of consecutive axial images were used to calculate cross-sectional area and (gross) volume. The k-means unsupervised algorithm was subsequently applied to the MR binary mask image array data with resultant volumes compared between groups.Older women and women with cancer had 37% and 48% less quadriceps muscle respectively than young women (p0.001). Application of k-means subtracted a significant 9%, 14% and 20% non-contractile tissue from the quadriceps of young, older and patient groups respectively (p0.001). There was a significant effect of group (i.e., cancer vs healthy) when controlling for age as a covariate (p = 0.003).K-means objectively separates contractile and non-contractile tissue components. Women with upper GI cancer have significant fatty infiltration throughout whole muscle groups which is maintained when controlling for age.

Lewis SJ, Barugh AJ, Greig CA, Saunders DH, Fitzsimons C, Dinan-Young S, Young A, Mead GE. Is fatigue after stroke associated with physical deconditioning? A cross-sectional study in ambulatory stroke survivors. Objective To determine the relationship between a measure of fatigue and 2 indices of physical fitness, lower limb extensor power (LLEP) and walking economy. Design This was a cross-sectional study of patients with stroke. Fatigue was assessed by vitality (VIT) score of the Medical Outcomes Study 36-Item Short-Form Health Survey version 2 (SF-36v2). LLEP of the unaffected limb was measured using a lower leg extensor power rig. Walking economy was calculated by measuring oxygen consumption (mL·kg –1 ·m –1 ) during walking at a comfortable speed. Bivariate analyses were performed relating VIT to indices of fitness. Multiple regression analyses were also performed and included age, sex, and either SF-36v2 emotional role function or SF-36v2 mental health, as predictors of VIT. Setting Community setting. Participants Participants (N=66; 36 men; mean age ± SD, 71.0±9.9y) were all community dwelling, had survived a stroke, were able to walk independently, and had completed their stroke rehabilitation. Interventions Not applicable Main Outcome Measures The main outcome measure is SF-36v2 (VIT), with walking economy and LLEP of the limb unaffected by the stroke being independent variables. Results Walking economy was not significantly related to VIT ( R =–.024, P =.86, n=60). LLEP was positively related to VIT in bivariate analysis ( R =.38, P =.003, n=58). After controlling for age, sex, and SF-36 emotional role function (or SF-36v2 mental health if the extreme outlier was excluded), LLEP remained a significant predictor of VIT. Conclusions We found an association between fatigue and reduced LLEP. If a larger study confirms these findings, it would support the need to develop and test interventions to increase LLEP as a treatment for fatigue after stroke.

Saunders DH, Greig CA, Young A, Mead GE. Association of activity limitations and lower-limb explosive extensor power in ambulatory people with stroke. Objective To determine whether the explosive lower-limb extensor power of the affected and unaffected sides, and any asymmetry, are associated with activity limitations after stroke. Design Cross-sectional observational study of baseline data from a randomized controlled trial. Setting Measurements made in a hospital clinical research facility. Participants Community-dwelling (N=66) subjects with stroke who were independently ambulatory. Subjects' mean age was 72±10 years. Interventions Not applicable. Main Outcome Measures The lower-limb extensor power of each lower limb (in W/kg), performance of specific functional activities (comfortable walking velocity, Functional Reach Test, chair-rise time, Timed Up & Go test), and global indices of activity limitation (FIM instrument, Rivermead Mobility Index, Nottingham Extended Activities of Daily Living). Results Low lower-limb extensor power in either lower limb was the principal factor from among the confounders we recorded that significantly ( R 2 range, .21–.46) predicted the limitation of specific functional activities, and low lower-limb extensor power in either lower limb was the principal predictive factor for global indices of activity limitation ( R 2 range, .13–.38). The degree of asymmetry of lower-limb extensor power between legs was low and had little or no predictive value. Conclusions In ambulatory persons with stroke, activity limitations are associated with deficits in lower-limb extensor power of both lower limbs, and not the severity of any residual asymmetry. These findings suggest that interventions to increase lower-limb extensor power in both lower limbs might reduce activity limitations after stroke.

BACKGROUND Sarcopenia, the loss of muscle mass and function with age, is associated with increased morbidity and mortality. Current understanding of the underlying mechanisms is limited. Glucocorticoids (GC) in excess cause muscle weakness and atrophy. We hypothesized that GC may contribute to sarcopenia through elevated circulating levels or increased glucocorticoid receptor (GR) signaling by increased expression of either GR or the GC-amplifying enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11βHSD1) in muscle. METHODS There were 82 participants; group 1 comprised 33 older men (mean age 70.2 years, SD 4.4) and 19 younger men (22.2 years, 1.7) and group 2 comprised 16 older men (79.1 years, 3.4) and 14 older women (80.1 years, 3.7). We measured muscle strength, mid-thigh cross-sectional area, fasting morning plasma cortisol, quadriceps muscle GR and 11βHSD1 mRNA, and urinary glucocorticoid metabolites. Data were analysed using multiple linear regression adjusting for age, gender and body size. RESULTS Muscle strength and size were not associated with plasma cortisol, total urinary glucocorticoids or the ratio of urinary 5β-tetrahydrocortisol +5α-tetrahydrocortisol to tetrahydrocortisone (an index of systemic 11βHSD activity). Muscle strength was associated with 11βHSD1 mRNA levels (β -0.35, p = 0.04), but GR mRNA levels were not significantly associated with muscle strength or size. CONCLUSION Although circulating levels of GC are not associated with muscle strength or size in either gender, increased cortisol generation within muscle by 11βHSD1 may contribute to loss of muscle strength with age, a key component of sarcopenia. Inhibition of 11βHSD1 may have therapeutic potential in sarcopenia.

The aim of this study was to test the safety, tolerability and efficacy of a novel combination of an anabolic β2-agonist and an appetite stimulant in patients with cancer cachexia. Thirteen patients (M/F 5:8) with advanced malignancy and involuntary weight loss received oral formoterol (80 μg/day) and megestrol acetate (480 mg/day) for up to 8 weeks. Quadriceps size (MRI), quadriceps and hand-grip strength, lower limb extensor power, physical activity and quality of life were measured at baseline and at 8 weeks. Response criteria were specified pre-trial, with a major response defined as an increase in muscle size ≥4 % or function ≥10 %. Six patients withdrew before 8 weeks, reflecting the frail, comorbid population. In contrast, six out of seven (86 %) patients completing the course achieved a major response for muscle size and/or function. In the six responders, mean quadriceps volume increased significantly (left 0.99 vs. 1.05 L, p = 0.012; right 1.02 vs. 1.06 L, p = 0.004). There was a trend towards an increase in quadriceps and handgrip strength (p > 0.05). The lack of appetite symptom score declined markedly (76.2 vs. 23.8; p = 0.005), indicating improvement. Adverse reactions were few, the commonest being tremor (eight reports), peripheral oedema (three), tachycardia (two) and dyspepsia (two). In this frail cohort with advanced cancer cachexia, an 8-week course of megestrol and formoterol in combination was safe and well tolerated. Muscle mass and/or function were improved to a clinically significant extent in most patients completing the course. This combination regimen warrants further investigation in larger, randomized trials.

Recent work suggests molecular cross-talk between adipose tissue and muscle that occurs through adipokines and myokines. These molecules act in an endocrine fashion to play an intricate role in regulating body composition in both health and disease. Studies in exercise physiology have focused on the molecular cross-talk between adipose tissue and muscle that occurs through adipokines and myokines and on the role these molecules may play in chronic diseases. Similarly, integrative physiology in obesity and diabetes has long emphasised the importance of chronic inflammation, increased adipocyte lipolysis, and increased levels of circulating free fatty acids in the adipose-muscle cross-talk that contributes to lipotoxicity and insulin resistance in muscle. Cachexia affects the majority of patients with advanced cancer and is associated with a reduction in treatment tolerance, response to therapy, quality of life, and duration of survival. Although cachexia in patients with cancer is characterized by systemic inflammation, increased lipolysis, insulin resistance, and reduced physical activity, there has been little effort to manipulate the integrative physiology of adipose tissue and muscle tissue for therapeutic gain.

Graeme J. Hankey, MD, FRACP, FRCP Section Editor Physical fitness is low after stroke and this may cause or exacerbate some common poststroke problems, including disability. It is not known whether improving physical fitness after stroke reduces disability or dependency. The primary aims of the review were to determine whether physical fitness training (cardiorespiratory and/or strength) after stroke reduces death, dependence, and disability at the end of intervention or follow-up. The secondary aims were to determine the effects of fitness training on physical fitness, mobility, physical function, health status and quality of life, mood, and the incidence of adverse events. ### Search Strategy We searched the Cochrane Stroke Group Trials Register (last searched March 2009), the Cochrane Central Register of Controlled Trials (Cochrane Library, 2007, Issue 1), MEDLINE (1966 to March …

Purpose: The mechanisms underlying muscle wasting in patients with cancer remain poorly understood, and consequently there remains an unmet clinical need for new biomarkers and treatment strategies. Experimental Design: Microarrays were used to examine the transcriptome in single biopsies from healthy controls (n = 6) and in paired biopsies [pre-resection baseline (weight-loss 7%) and 8 month post-resection follow-up (disease-free/weight-stable for previous 2 months)] from quadriceps muscle of patients with upper gastrointestinal cancer (UGIC; n = 12). Results: Before surgery, 1,868 genes were regulated compared with follow-up (false discovery rate, 6%). Ontology analysis showed that regulated genes belonged to both anabolic and catabolic biologic processes with overwhelming downregulation in baseline samples. No literature-derived genes from preclinical cancer cachexia models showed higher expression in baseline muscle. Comparison with healthy control muscle (n = 6) revealed that despite differences in the transcriptome at baseline (941 genes regulated), the muscle of patients at follow-up was similar to control muscle (2 genes regulated). Physical activity (step count per day) did not differ between the baseline and follow-up periods (P = 0.9), indicating that gene expression differences reflected the removal of the cancer rather than altered physical activity levels. Comparative gene expression analysis using exercise training signatures supported this interpretation. Conclusions: Metabolic and protein turnover–related pathways are suppressed in weight-losing patients with UGIC whereas removal of the cancer appears to facilitate a return to a healthy state, independent of changes in the level of physical activity. Clin Cancer Res; 18(10); 2817–27. ©2012 AACR.

Summary Background & aims There is a sparsity of data on the impact of cachexia on human muscle function. This study examined the relationship between cachexia, quality of life and the mass/function/mechanical quality of lower limb skeletal muscle in gastrointestinal cancer patients. Methods Quadriceps strength and lower limb power were measured in 54 patients with gastrointestinal cancer ( n = 24 ≥ 10% weight-loss) and 18 healthy controls. Quadriceps cross-sectional area was measured in 33/54 patients and in all controls using MRI. Muscle mechanical quality was defined as quadriceps strength/unit quadriceps cross-sectional area. Quality of life was assessed using the EORTC QLQ-C30. Patients with weight-loss ≥10% were classified as cachectic. Results In male cachectic patients, quadriceps strength ( p = 0.003), lower limb power ( p = 0.026), quadriceps cross-sectional area ( p = 0.019) and muscle quality ( p = 0.008) were reduced compared with controls. In female cachectic patients, quadriceps strength ( p = 0.001) and muscle quality ( p = 0.001) were reduced compared with controls. Physical function ( p = 0.013) and fatigue ( p = 0.004) quality of life scores were reduced in male cachectic compared with non-cachectic patients, but not in females. Conclusions Muscle quality is reduced in cancer patients. The degree of impairment of lower limb muscle mass, quality and function and the impact on quality of life varies with weight-loss and sex.

Sarcopenia is the loss of muscle size and function during ageing. The aim of this study was to test whether serum concentrations of myostatin and interacting proteins (GASP-1, FLRG, and follistatin) differed between young and elderly sarcopenic men. Isometric knee extensor maximal voluntary contraction and quadriceps cross-sectional area (magnetic resonance imaging measurement) were significantly higher in young (22 ± 2 years; 266 ± 54 N/m; 8,686 ± 1,154 mm(2)) than in mildly sarcopenic (69 ± 3 years; 183 ± 17 N/m; 6,621±718 mm(2)) and severely sarcopenic men (76 ± 6 years; 127 ± 23 N/m; 5,846 ± 591 mm(2)), respectively (p ≤ .01 for all comparisons). There was a trend (p = .06) toward higher FLRG in young (20 ± 8 ng/mL) than in mildly (15 ± 6 ng/mL) and severely sarcopenic men (17 ± 8 ng/mL). Myostatin, follistatin, GASP-1, tumor necrosis factor α, and interleukin-6 did not differ significantly. Insulin-like growth factor-1 and free testosterone were both significantly lower in sarcopenic men (p < .001). This suggests that altered serum concentrations of myostatin and myostatin-interacting proteins are not contributing to sarcopenia with the possible exception of FLRG. ispartof: Journals of Gerontology A, Biological Sciences and Medical Sciences vol:66 issue:6 pages:620-626 ispartof: location:United States status: published

BACKGROUND: Intramyocellular lipids are an important source of fuel for mitochondrial fat oxidation and play an important role in intramuscular lipid homeostasis. We hypothesised that due to the phenotype associated with cancer cachexia, there would exist an association between increasing weight loss and the number/size of intramyocellular lipid droplets. METHODS: Nineteen cancer patients and 6 controls undergoing surgery were recruited. A rectus abdominis biopsy was performed and processed for transmission electron microscopy (TEM). The number of intramyocellular lipid droplets and lipid droplet diameter were calculated from the TEM images. CT scans, performed as part of patients' routine care, were analysed to determine amount of adipose (intermuscular, visceral and subcutaneous) and muscle tissue. RESULTS: Compared with controls, cancer patients had increased numbers of lipid droplets (mean (SD) 1.8 (1.9) vs. 6.4 (9.1) per ×2,650 field, respectively, p = 0.036). Mean (SD) lipid droplet diameter was also higher in cancer patients compared with controls (0.42 (0.13) vs. 0.24 (0.21) μm, p = 0.015). Mean lipid droplet count correlated positively with the severity of weight loss (R = 0.51, p = 0.025) and negatively with CT-derived measures of intermuscular fat (R = -0.53, p = 0.022) and visceral fat (R = -0.51, p = 0.029). CONCLUSIONS: This study suggests that the number and size of intramyocellular lipid droplets is increased in the presence of cancer and increases further with weight loss/loss of adipose mass in other body compartments.

Purpose: We have investigated the use of human urine as a non-invasive medium to screen for molecular biomarkers of carcinomas of the upper gastrointestinal (uGI) tract using SELDI-TOF-MS. Experimental design: A total of 120 urine specimens from 60 control and 60 uGI cancer patients were analysed to establish a potential biomarker fingerprint for the weak cation exchanger CM10 chip surface, which was validated by blind testing using a further 59 samples from 33 control and 26 uGI cancer patients. Results: Using Biomarker Pattern software, we established a model with a sensitivity of 98% and specificity of 95% for the learning sample set, and a sensitivity of 96% and specificity of 72% for the validation data set. Model variable importance included six peptides with m/z of 10 230, 10 436, 10 574, 10 311, 10 467, and 1 0118 of which the 10 230 molecular species was the main decider (sensitivity 86% and specificity 80%). Initial protein database searching identified 10 230 as S100-A6, 10 436 as S100-P, 10 467 as S100-A9, and 10 574 as S100-A12 of which S100-A6 and S100-A9 were confirmed by Western blotting. Conclusions and clinical relevance: We have demonstrated that SELDI-TOF-MS as a screening tool is a rapid and valid methodology in the search for urinary cancer biomarkers, and is potentially useful in defining and consolidating biomarker patterns for uGI cancer screening.

Sarcopenia (muscle loss with ageing) adversely affects mobility and stability and increases risk of falls – and mortality – after hip or femur fracture. Developing effective interventions has been a major goal for 30 years but so far only resistance exercise has shown any real benefit. However, this may change with the advent of drug treatments under development, like non-steroidal selective androgen receptor modulators (SARMS) and anti-myostatin antibodies. One promising but different approach has emerged from the increasingly strong evidence that sarcopenia is associated with, and may even be caused by, inflammation of muscle and the blood vessels supplying it. Older people with marked muscle wasting, tend to carry a high burden of pro-inflammatory markers (e.g. C-reactive peptide and cytokines, such as tumour necrosis factor alpha (TNF-α) and interleukins (including interleukin-6 (IL-6), IL-1a, IL-8 and IL-10); the plasma titre of these may even predict subsequent disability. There is, therefore, much interest in potential anti-inflammatory treatments of sarcopenia; the idea of being able to take a pill (especially a cheap one) to prevent muscle loss is tantalizing. Isabelle Rieu and colleagues, from the laboratory of Dominque Dardevet at the French National Institute for Agricultural Research (INRA) in Clermont-Ferrand, have produced important new evidence in a recent issue of The Journal of Physiology (Rieu et al. 2009) bolstering the argument that research on the possible effects of anti-inflammatories on the regulation of muscle mass is promising. In their elegant study, the French scientists supplemented the diet of old (20 months) rats for 5 months with 30 mg kg−1 day−1 of the non-steroidal anti-inflammatory drug (NSAID) ibuprofen (IBU). In these rats (and in controls allowed to develop spontaneous low-grade inflammation as they aged) markers of inflammation in plasma, the rate of muscle protein synthesis (MPS) in vivo and muscle protein breakdown (MPB) in vitro were measured, together with the phosphorylation of kinases in the mTORc1 pathway (controlling translation from mRNA) and of the muscle transcription factor FOXO-3a (which regulates mRNA expression of ubiquitin ligases heading the ubiquitin–ATP-dependent proteolysis pathway (UPP)). After IBU treatment, 25-month-old rats showed less muscle wasting than untreated controls, which had more markers of inflammation in plasma. The apparent underlying mechanisms (see Fig. 1) involve modification of both MPS and MPB – not in the fasted state but rather after feeding, when normally MPS is raised by essential amino acids and MPB is inhibited by insulin. Whereas there were no demonstrable differences in either arm of protein turnover in the postabsorptive state, the non-treated rats showed the now well-recognized (Mosoni et al. 1995; Cuthbertson et al. 2005; Wilkes et al. 2009) phenomenon of anabolic blunting of both MPS and MPB on feeding, which was abolished in the IBU-treated animals. Maybe at last the simplistic idea of uncontrolled proteolysis eating up ageing muscle can be laid to rest. Figure 1 Potential mechanisms by which muscle protein maintenance may be influenced by the anti-inflammatory agents, ibuprofen and fish oil This study provides new evidence of one cause of the anabolic blunting of ageing as inflammation and demonstrates originally that it can be ameliorated by an NSAID. One fascinating piece of data is unexpected – the finding that FOXO-3a phosphorylation is increased in muscle of IBU-treated post-prandial rats compared to that of controls. This probably resulted in a nuclear-barring of phosphorylated FOXO-3a, providing a mechanistic explanation for the observed decreased MPB. Another surprising result, given that elsewhere (especially in human muscle), anabolic blunting is associated with decreased phosphorylation in the Akt/mTORc1 signalling family, was the lack of evidence of this in inflamed rats. Here again, it seems, we lack enough information on the control of muscle protein turnover to predict accurately the behaviour of the regulatory signalling system, as previously found in human muscle (Greenhaff et al. 2008). The mechanism of IBU action almost certainly involves decreasing throughput in the NFκB pathway via actions consequent to decreasing COX2 activity, with a subsequent decrease of PGE2-α (a lipid signalling molecule first shown to be catabolic by Robert Palmer and Peter Reeds at the Rowett Research Institute, 26 years ago; Reeds & Palmer, 1983). Whereas the details of the exact mechanisms (see Fig. 1) remain speculative, it is fascinating that the evidence (e.g. see Ryan et al. 2009) piling up in favour of an anabolic effect of fish oils (which also decrease muscle PGE2-α production) may involve similar distal mechanisms in ameliorating muscle wasting. How ironic it would be if big pharma, investing massively in SARMS and anti-myostatin antibodies were scooped by geriatricians prescribing nothing more expensive that daily NSAIDS (albeit judiciously, with a proton-pump inhibitor maybe?) – and a kipper (or a bagel with extra lox) twice a week! Is that, and subsequent development, feasible? Just look at Dardevet's track-record of prefiguring discoveries in human muscle with careful studies in rats (Dardevet et al. 2000). He has form and it's a good bet that he will romp home again.

The objectives of this study were to (1) evaluate the suitability of "comfortable" self-paced walking as a mode of exercise to study VO(2) kinetics, and (2) to investigate VO(2) kinetics after hip fracture using self-paced walking as the exercise mode. The study took place in a Scottish rehabilitation hospital physiotherapy gymnasium [hip fracture (HF) group] and a Scottish University Gymnasium [young (Y) and healthy elderly (HE) groups]. Fifteen women after HF (median age 81 years) and five Y and five older HE women (median ages 22 and 78 years, respectively) took part in the study. Volunteers completed three repeats of 3 min of "comfortable" self-paced walking on two occasions. The ensemble averaged VO(2) response from walks 2 and 3 on visits 1 and 2 were combined and characterised using nonlinear regression techniques to derive a Mean Response Time (MRT). Self-paced walking was described as "constant-load" exercise (coefficient of variation of lap speeds of