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INTRODUCTION: Flight-related neck pain (FRNP) is a frequently reported musculoskeletal complaint among military helicopter aircrew. However, despite its prevalence and suspected causes, little is known of the underpinning pain mechanisms or the impact of neck pain on aircrews in-flight task performance. The biopsychosocial (BPS) approach to health, combined with the contemporary conceptualization of musculoskeletal pain, in which injury and pain are not necessarily synonymous, provides a relatively new holistic framework within which to consider the problem of FRNP in military helicopter aircrew. Combining these concepts, a new conceptual model is proposed to illustrate how biopsychosocial factors may influence pain perception, potentially affecting aircrews capacity to process information and, therefore, threatening in-flight task performance. Recommendations are made for considering the underlying pain mechanisms of FRNP to aid prognoses and guide the development of holistic evidence-based countermeasures for FRNP in military helicopter aircrew. Development of instruments able to measure psychosocial factors, such as self-efficacy and functional ability, validated in the military helicopter aircrew population, would assist this task.Vail RE, Harridge SDR, Hodkinson PD, Green NDC, Pavlou M. A novel biopsychosocial approach to neck pain in military helicopter aircrew. Aerosp Med Hum Perform. 2021; 92(5):333341.

During voluntary muscle contractions, force output is characterized by constant inherent fluctuations, which can be quantified either according to their magnitude or temporal structure, that is, complexity. The presence of such fluctuations when targeting a set force indicates that control of force is not perfectly accurate, which can have significant implications for task performance. Compared to young adults, older adults demonstrate a greater magnitude and lower complexity in force fluctuations, indicative of decreased steadiness, and adaptability of force output, respectively. The nature of this loss-of-force control depends not only on the age of the individual but also on the muscle group performing the task, the intensity and type of contraction and whether the task is performed with additional cognitive load. Importantly, this age-associated loss-of-force control is correlated with decreased performance in a range of activities of daily living and is speculated to be of greater importance for functional capacity than age-associated decreases in maximal strength. Fortunately, there is evidence that acute physical activity interventions can reverse the loss-of-force control in older individuals, though whether this translates to improved functional performance and whether lifelong physical activity can protect against the changes have yet to be established. A number of mechanisms, related to both motor unit properties and the behavior of motor unit populations, have been proposed for the age-associated changes in force fluctuations. It is likely, though, that age-associated changes in force control are related to increased common fluctuations in the discharge times of motor units.

Creatine dilution (D 3-cr) is a technique for estimating total skeletal muscle mass (SMM) with practical utility, but has not been applied in athletic populations where body composition may differ to that in the normal population. This study aimed to assess the agreement between SMM derived from both D 3-cr and that obtained from whole-body magnetic resonance imaging (MRI) in 15 male and 5 female national level kayakers (stature: 182.0 ± 13.1 and 170.0 ± 9.0 cm; body mass: 80.6 ± 9.9 and 66.4 ± 6.0 kg; V̇O 2peak: 56.5 ± 7.0 and 49.6 ± 4.4 mL kg −1 min −1, mean ± SD). SMM was determined following 60 mg of dosed D 3-cr and analysis of expelled urine collected on four subsequent days for creatine, creatinine, D 3-cr, and D 3-creatinine using liquid chromatography/mass spectroscopy. SMM was then estimated by assuming a creatine pool size of 4.3 g/kg. During the same time period, a whole-body MRI was undertaken to derive SMM from the analysis of multiple slices taken across the body. A strong positive correlation (F = 74.32; R = 0.90; P 3-cr SMM was found to be significantly higher (43.3 ± 6.8 kg) when compared with MRI (36.3 ± 5.8 kg, P 3-cr has potential utility in athletes, as referenced against MRI, but show that assumptions regarding creatine pool size need to be carefully considered.

As the inherent ageing process affects every facet of biology, physiology could be considered as the study of the healthy human ageing process. Where biological health is affected by lifestyle, the continual and continuing interaction of this process with physical activity and other lifestyle choices determine whether the ageing trajectory is toward health or disease. The presentation of both these states is further modified in individuals by the interaction of inherent physiological heterogeneity and the heterogeneity associated with responses and adaptions to exercise. The range of heterogeneity in healthy physiology is circumscribed by the necessity to conform to that of the human species. Our hypothesis is that, when sufficient exercise is present, these multiple interactions appear to produce an ageing profile that, while functional ability is in decline, remains synchronous, coherent, and integrated throughout most of life. In the absence of sufficient physical activity, physiology over time is gradually deteriorating toward the production of a lifestyle disease. Here, the ageing process, interacting with individual physiological heterogeneity, probably determines the age of presentation of a disease as well as the order of presentation of subsequent diseases. In this article, we discuss this hypothesis and related concepts in the context of the trajectory of healthy and non-healthy human ageing.

Chemically skinned fibres allow the study of human muscle contractile function in vitro. A particularly important parameter is specific force (SF), that is, maximal isometric force divided by cross-sectional area, representing contractile quality. Although SF varies substantially between studies, the magnitude and cause of this variability remains puzzling. Here, we aimed to summarize and explore the cause of variability in SF between studies. A systematic search was conducted in Medline, Embase and Web of Science databases in June 2020, yielding 137 data sets from 61 publications which studied healthy, young adults. Five-fold differences in mean SF data were observed. Adjustments to the reported data for key methodological differences allowed between-study comparisons to be made. However, adjustment for fibre shape, swelling and sarcomere length failed to significantly reduce SF variance (I2 = 96%). Interestingly, grouping papers based on shared authorship did reveal consistency within research groups. In addition, lower SF was found to be associated with higher phosphocreatine concentrations in the fibre activating solution and with Triton X-100 being used as a skinning agent. Although the analysis showed variance across the literature, the ratio of SF in single fibres containing myosin heavy chain isoforms IIA or I was found to be consistent across research groups. In conclusion, whilst the skinned fibre technique is reliable for studying in vitro force generation of single fibres, the composition of the solution used to activate fibres, which differs between research groups, is likely to heavily influence SF values.

INTRODUCTION: Physical conditioning may improve aircrew performance during exposure to high +Gz acceleration, although few studies have directly assessed this. The present study investigated the effects of a 12-wk Aircrew Conditioning Programme (ACP) on markers of G tolerance. The ACP comprises aerobic and muscle strengthening exercise performed twice weekly and targets improved fitness and reduced injury risk.METHODS: There were 36 UK Royal Air Force and Royal Navy aircrew who volunteered; 17 performed the ACP (Ex) and 19 acted as a control group (Con). Centrifuge testing was performed before and after the intervention. Relaxed G tolerance (RGT) and straining G tolerance (SGT), which had the addition of muscle tensing, were assessed. G endurance was also determined via repeated simulated air combat maneuvers (SACMs). During these centrifuge runs a number of physiological variables were recorded.RESULTS: During the G profile to determine RGT, neither RGT, HR, nor blood pressure responses were affected by the ACP. During SGT profiles, a lower HR at a given +Gz (+5.5 Gz) level following the ACP was observed (Ex: pre 146.0 ± 4.4, post 136.9 ± 5.6 bpm; Con: pre 148.0 ± 3.2, post 153.1 ± 3.3 bpm). BP was maintained and there was a tendency toward an improved SGT. The ACP increased the proportion of individuals completing the number of SACM profiles, although no meaningful differences were found between groups in other variables.CONCLUSION: Overall the ACP has no negative effect on RGT, reduced the physiological strain associated with a given level of +Gz (during SGT), and tended to improve the ability to tolerate repeated Gz exposure.Slungaard E, Pollock RD, Stevenson AT, Green NDC, Newham DJ, Harridge SDR. Aircrew conditioning programme impact on +Gz tolerance. Aerosp Med Hum Perform. 2019; 90(9):764-773.

Remodelling of the immune system with age — immunosenescence — is a substantial contributor to poor health in older adults, with increasing risk of infections, cancer and chronic inflammatory disease contributing to age-related multi-morbidity. What is seldom considered when examining the immune response of an aged individual is that the immune system is profoundly influenced by physical activity. Habitual physical activity levels decline with age, with significant consequences for muscle mass and function. Skeletal muscle is a major immune regulatory organ and generates a range of proteins, termed myokines, which have anti-inflammatory and immunoprotective effects. Several studies indicate that maintaining physical activity has immune benefits in older adults, for example, it reduces the systemic inflammation associated with chronic age-related diseases. Here, we discuss how physical activity can prevent or ameliorate age-related multi-morbidity by boosting immune function, and we consider whether physical activity could improve immunotherapy outcomes in age-related conditions such as cancer.

This brief review focuses on the relationships and interactions between human ageing, exercise and physiological function. It explores the importance of the selection of participants for ageing research, the strengths and deficiencies of both cross‐sectional and longitudinal studies and the complexities involved in understanding time‐dependent, lifelong physiological processes. As being physically active is crucial to fostering healthy ageing, it is essential that participants in health and ageing research are defined in terms of their physical activity / exercise status as well as other lifestyle factors. Comparisons of exercisers with non‐exercisers has suggested that there is a mosaic of regulation of ageing both within and across physiological systems. We suggest that four broad categories exist which encompass this regulation. These are i) systems and indices that are age‐dependent, but activity independent; ii) systems that are age‐dependent, but also malleable by exercise; iii) systems that are not age affected but are altered by exercise and iv) systems that are neither age nor activity dependent. We briefly explore the concept of a mosaic of regulation in a selection of physiological systems that include skeletal muscle, the immune and endocrine systems and cognitive function and how these categories fit within the broad framework of understanding the physiology of human ageing.Schematic to depict how healthy or diseased ageing phenotypes are the product of the interaction and regulation of physiological systems that can broadly be grouped into 4 categories on the basis of their malleability or otherwise to exercise and to the ageing process.

6 p., The authors belong to the ESA Space Omics Topical Team funded by the ESA grant/contract 4000131202/20/NL/PG/pt “Space Omics: Towards an integrated ESA/NASA –omics database for spaceflight and ground facilities experiments” to RH.

Background: Exercise training improves cardiometabolic outcomes in ‘mean terms’, but little information is available in children about the impact of the frequency/week and the wide inter-individual variability to exercise training reported in adults. Objectives: We compared the effects of resistance training (RT) and high-intensity interval training (HIT), and ‘high’ and ‘low’ frequency of training/week, for their effectiveness in decreasing insulin resistance (IR) levels in schoolchildren. A second aim was to decscribe and compare the prevalence of non-responders (NRs) between the different frequencies of training protocol. Methods: Fifty-three schoolchildren with IR were randomly assigned into four groups: RT at high frequency (three times/week), HIT at high frequency, RT at a low frequency (two times/week) and HIT at low frequency. The intervention lasted 6 weeks. Blood samples and body composition, blood pressure and performance measurements were taken before and after the intervention. Results: The prevalence of NRs was similar between the RTHF and HITHF (25.0% vs. 25.0%, P > 0.05) and RTLF and HITLF groups (20.0% vs. 46.6%, P = 0.174) for decreasing homeostasis model assessment of IR. However, significant differences in the prevalence of NRs were detected between RTHF and HITHF groups in fasting glucose (FGL) (18.7% vs. 58.3%, P less than 0.031). Conclusions: Both RT and HIT improves the glucose control parameters in schoolchildren over 6 weeks, but only HIT is independent of a high or low frequency of training/week. The prevalence of NRs is similar for decreasing homeostasis model assessment of IR comparing each exercise mode in high vs. low frequency/week. However, both high- and low-frequency RT and HIT results in differences in the prevalence of NRs for FGL and other cardiometabolic and performance outcomes. © 2018 World Obesity Federation

International audience; At high altitude oxygen delivery to the tissues is impaired leading to oxygen insufficiency (hypoxia). Acclimatisation requires adjustment to tissue metabolism, the details of which remain incompletely understood. Here, metabolic responses to progressive environmental hypoxia were assessed through metabolomic and lipidomic profiling of human plasma taken from 198 human participants before and during an ascent to Everest Base Camp (5,300 m). Aqueous and lipid fractions of plasma were separated and analysed using proton (1 H)-nuclear magnetic resonance spectroscopy and direct infusion mass spectrometry, respectively. Bayesian robust hierarchical regression revealed decreasing isoleucine with ascent alongside increasing lactate and decreasing glucose, which may point towards increased glycolytic rate. Changes in the lipid profile with ascent included a decrease in triglycerides (48-50 carbons) associated with de novo lipogenesis, alongside increases in circulating levels of the most abundant free fatty acids (palmitic, linoleic and oleic acids). Together, this may be indicative of fat store mobilisation. This study provides the first broad metabolomic account of progressive exposure to environmental hypobaric hypoxia in healthy humans. Decreased isoleucine is of particular interest as a potential contributor to muscle catabolism observed with exposure to hypoxia at altitude. Substantial changes in lipid metabolism may represent important metabolic responses to sub-acute exposure to environmental hypoxia. Reduced cellular oxygen availability (hypoxia) is a feature of many disease states. Oxygen delivery may be globally impaired by diseases of the heart or lung, or by anaemia (in which the concentration of oxygen-carrying haemoglobin is reduced); or regionally or locally impaired by macrovascular and microvascular disease respectively 1,2. Diffusion of oxygen in the lungs and/or tissues may be impaired through accumulation of parenchymal fluid and/

Introduction Exposure to sustained +Gz acceleration with inadequate G protection can result in G-induced loss of consciousness (G-LOC) or almost loss of consciousness (A-LOC). The UK Royal Air Force (RAF) last conducted a survey of G-LOC within their military aircrew in 2005 with interventions subsequently introduced. The aim of this study was to repeat the 2005 survey in order to evaluate the impact of those interventions. Methods An anonymous questionnaire requesting details of G-LOC and A-LOC events was mailed to all RAF pilots (N = 1878) and weapons systems operators (WSOs) (N = 473), irrespective of aircraft currently flown. Results The questionnaire was returned by 809 aircrew (34.4% response rate). There were 120 (14.8%) aircrew who reported at least one episode of G-LOC and 260 (32.2%) reported at least one episode of A-LOC. The reported prevalence of G-LOC in the previous 2005 survey was 20.1% (N = 454). There was an increased reporting of G-LOC in the Hawk, Tucano, and Grob Tutor aircraft, with 5 G-LOC and 19 A-LOC events reported in the Grob Tutor compared to none in 2005. Discussion The prevalence of reported G-LOC has decreased in the surveyed populations, which may be due to the introduction of centrifuge training, but also may be influenced by patterns of G exposure and other factors. Scope for further reduction remains through correct execution of the anti-G straining maneuver (AGSM) with centrifuge training early in flying training and use of a structured conditioning program to increase the general strength of muscles involved in the AGSM.Slungaard E, McLeod J, Green NDC, Kiran A, Newham DJ, Harridge SDR. Incidence of G-induced loss of consciousness and almost loss of consciousness in the Royal Air Force. Aerosp Med Hum Perform. 2017; 88(6):550-555.

Analysis of world record performances by master athletes suggests an essentially linear decline with age until around the eighth decade after which performance decline accelerates. Because these records are obtained from highly trained individuals they can be viewed as being reflective of the diminution of integrative physiological prowess that occurs solely as a result of ageing, unaffected by the confounding effects of inactivity. It can also be argued that these performance profiles mirror and provide an insight into the trajectory of the physiology of the human ageing process. Here we propose a set point theory that hypothesises that a given threshold of physical activity is needed to age optimally and to maximise the 'healthspan'. Exercising at levels below the set point will result in ageing being contaminated by the unpredictable and pathological effects of inactivity. Exercise above this threshold stimulates adaptations towards maximising athletic performance, but is unlikely to have further beneficial effects on health. Thus the decades-long, controlled diminution in athletic performance, should not be seen as a disease process. The ageing process is separate from, and independent of, exercise-mediated processes that maintain or adapt physiological function. Whether an understanding of these mechanisms will also help uncover mechanisms underpinning the ageing process itself is open to question. However, any model which does not take into account the effects of activity will not adequately describe the inherent ageing process.

The age-associated reduction in muscle mass is well characterized; however, less is known regarding the mechanisms responsible for the decline in oxidative capacity also observed with advancing age. The purpose of the current study was therefore to compare mitochondrial gene expression and protein content between young and old recreationally active, and older highly active individuals. Muscle biopsies were obtained from the vastus lateralis of young males (YG: 22 ± 3 years) and older (OG: 67 ± 2 years) males not previously engaged in formal exercise and older male master cyclists (OT: 65 ± 5 years) who had undertaken cycling exercise for 32 ± 17 years. Comparison of gene expression between YG, OG, and OT groups revealed greater expression of mitochondrial-related genes, namely, electron transport chain (ETC) complexes II, III, and IV (p < .05) in OT compared with YG and OG. Gene expression of mitofusion (MFN)-1/2, mitochondrial fusion genes, was greater in OT compared with OG (p < .05). Similarly, protein content of ETC complexes I, II, and IV was significantly greater in OT compared with both YG and OG (p < .001). Protein content of peroxisome proliferator-activated receptor gamma, coactivator 1 α (PGC-1α), was greater in OT compared with YG and OG (p < .001). Our results suggest that the aging process per se is not associated with a decline in gene expression and protein content of ETC complexes. Mitochondrial-related gene expression and protein content are substantially greater in OT, suggesting that exercise-mediated increases in mitochondrial content can be maintained into later life.

From 19th to 22nd November 2018, 26 researchers representing nine countries and a variety of academic disciplines met in Snekkersten, Denmark, to reach evidence-based consensus about physical activity and older adults. It was recognised that the term ‘older adults’ represents a highly heterogeneous population. It encompasses those that remain highly active and healthy throughout the life-course with a high intrinsic capacity to the very old and frail with low intrinsic capacity. The consensus is drawn from a wide range of research methodologies within epidemiology, medicine, physiology, neuroscience, psychology and sociology, recognising the strength and limitations of each of the methods. Much of the evidence presented in the statements is based on longitudinal associations from observational and randomised controlled intervention studies, as well as quantitative and qualitative social studies in relatively healthy community-dwelling older adults. Nevertheless, we also considered research with frail older adults and those with age-associated neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, and in a few cases molecular and cellular outcome measures from animal studies. The consensus statements distinguish between physical activity and exercise. Physical activity is used as an umbrella term that includes both structured and unstructured forms of leisure, transport, domestic and work-related activities. Physical activity entails body movement that increases energy expenditure relative to rest, and is often characterised in terms of intensity from light, to moderate to vigorous. Exercise is defined as a subset of structured physical activities that are more specifically designed to improve cardiorespiratory fitness, cognitive function, flexibility balance, strength and/or power. This statement presents the consensus on the effects of physical activity on older adults’ fitness, health, cognitive functioning, functional capacity, engagement, motivation, psychological well-being and social inclusion. It also covers the consensus on physical activity implementation strategies. While it is recognised that adverse events can occur during exercise, the risk can be minimised by carefully choosing the type of activity undertaken and by consultation with the individual’s physician when warranted, for example, when the individual is frail, has a number of co-morbidities, or has exercise-related symptoms, such as chest pain, heart arrhythmia or dizziness. The consensus was obtained through an iterative process that began with the presentation of the state-of-the-science in each domain, followed by group and plenary discussions. Ultimately, the participants reached agreement on the 30-item consensus statements.

ObjectivesTo characterise the sketetal muscle metabolic phenotype during early critical illness.MethodsVastus lateralis muscle biopsies and serum samples (days 1 and 7) were obtained from 63 intensive care patients (59% male, 54.7±18.0 years, Acute Physiology and Chronic Health Evaluation II score 23.5±6.5).Measurements and main resultsFrom day 1 to 7, there was a reduction in mitochondrial beta-oxidation enzyme concentrations, mitochondrial biogenesis markers (PGC1α messenger mRNA expression (−27.4CN (95% CI −123.9 to 14.3); n=23; p=0.025) and mitochondrial DNA copy number (−1859CN (IQR −5557–1325); n=35; p=0.032). Intramuscular ATP content was reduced compared tocompared with controls on day 1 (17.7mmol/kg /dry weight (dw) (95% CI 15.3 to 20.0) vs. 21.7 mmol/kg /dw (95% CI 20.4 to 22.9); pConclusionsDecreased mitochondrial biogenesis and dysregulated lipid oxidation contribute to compromised skeletal muscle bioenergetic status. In addition, intramuscular inflammation was associated with impaired anabolic recovery with lipid delivery observed as bioenergetically inert. Future clinical work will focus on these key areas to ameliorate acute skeletal muscle wasting.Trial registration numberNCT01106300.

Introduction The prevalence of flight-related neck pain in all Royal Air Force (RAF) aircrew is 66% and 70% in UK fast-jet aircrew. The RAF Aircrew Conditioning Programme (ACP) has been designed to enhance pilot performance through reducing fatigue and strain injuries, particularly to the neck. Content validity of the ACP was assessed to determine the appropriateness for delivery to aircrew. Methods Six international medical experts reviewed level two of the ACP, which is delivered to student aircrew who have completed basic instruction in cervical spine stability, core stability and initial technique instruction for strength training. Content validity on overall exercise approach (5 items) and specific exercise session (24 items) was rated on a 4-point Likert-type ordinal scale for Relevance and Simplicity. Four reviewers had experience of delivering an exercise program to aircrew. The item-content validity index (I-CVI) was the proportion of experts rating an item/exercise as acceptable (score 3-4) while protocol-CVI was the average I-CVI across items. Results Of the suggested exercise sessions, 20 reached an excellent I-CVI (1.00) for Relevance (4 reached acceptable I-CVI (0.83)), and 21 reached an excellent I-CVI (1.00) for Simplicity (3 reached acceptable I-CVI (0.83)). Protocol-CVI for the ACP was excellent for Relevance (0.90) and good for Simplicity (0.83). The need for sufficient supervision during the exercises was recommended for safe exercise execution and to maintain adherence. Conclusion The ACP demonstrated excellent relevance for the target population. The aircrew require additional supervision with the more complex neck exercises to enhance simplicity with the ACP.Slungaard E, Green NDC, Newham DJ, Harridge SDR. Content validity of level two of the Royal Air Force Aircrew Conditioning Program. Aerosp Med Hum Perform. 2018; 89(10):896-904.

Arguably the best available depictions of the global physiological changes produced by age are the profiles of world record performance times in swimming, athletics, and cycling, depicting the trajectory of decline in maximal integrated physiological performance capability. The curves suggest that the aging process produces a synchronized, controlled decrease in physiological performance over the human lifespan. The shape of the performance profile by age is essentially independent of discipline, distance, or phenotype. Importantly, the specific times of performance are not the driving force in the production of the shape of the declining performance profile. We suggest that in these highly trained individuals the shape of the curve is generated by the aging process operating on a physiology optimized for any given age. We hypothesize that with adequate training this same profile and trajectory, but with lower performance times, would be generated by all individuals who engage in sufficient physical activity/exercise. Unlike performance, data obtained from examining individual physiological systems or tissues do not give information on the unceasing and changing global integrating functions of the aging process. However, these data do give valuable information about the integrity of physiological systems at a particular age and allow a direct comparison to be made between the effects of inactivity and physical activity/exercise. Being physically active has been shown to have global protective effects on physiological systems and thus facilitates the aging process by maintaining physiological integrity. There is emerging evidence which suggests that physiological regulation of aging may be multi-compartmentalized. We do not advocate exercise as a panacea, but all the evidence indicates that being physically active and exercising is far superior to any other alternative for achieving optimal aging.

BACKGROUND: Loss of skeletal muscle mass and muscle weakness are common in a variety of clinical conditions with both wasting and weakness associated with an impairment of physical function. β-Hydroxy-β-methylbutyrate (HMB) is a nutrition supplement that has been shown to favorably influence muscle protein turnover and thus potentially plays a role in ameliorating skeletal muscle wasting and weakness. OBJECTIVES: The aim of this study was to investigate the efficacy of HMB alone, or supplements containing HMB, on skeletal muscle mass and physical function in a variety of clinical conditions characterized by loss of skeletal muscle mass and weakness. METHODS: A systematic review and meta-analysis of randomized controlled trials reporting outcomes of muscle mass, strength, and physical function was performed. Two reviewers independently performed screening, data extraction, and risk-of-bias assessment. Outcome data were synthesized through meta-analysis with the use of a random-effects model and data presented as standardized mean differences (SMDs). RESULTS: Fifteen randomized controlled trials were included, involving 2137 patients. Meta-analysis revealed some evidence to support the effect of HMB alone, or supplements containing HMB, on increasing skeletal muscle mass (SMD = 0.25; 95% CI: -0.00, 0.50; z = 1.93; P = 0.05; I2 = 58%) and strong evidence to support improving muscle strength (SMD = 0.31; 95% CI: 0.12, 0.50; z = 3.25; P = 0.001; I2 = 0%). Effect sizes were small. No effect on bodyweight (SMD = 0.16; 95% CI: -0.08, 0.41; z = 1.34; P = 0.18; I2 = 67%) or any other outcome was found. No study was considered to have low risk of bias in all categories. CONCLUSION: HMB, and supplements containing HMB, increased muscle mass and strength in a variety of clinical conditions, although the effect size was small. Given the bias associated with many of the included studies, further high-quality studies should be undertaken to enable interpretation and translation into clinical practice. The trial was registered on PROSPERO as CRD42017058517.

At high altitude oxygen delivery to the tissues is impaired leading to oxygen insufficiency (hypoxia). Acclimatisation requires adjustment to tissue metabolism, the details of which remain incompletely understood. Here, metabolic responses to progressive environmental hypoxia were assessed through metabolomic and lipidomic profiling of human plasma taken from 198 human participants before and during an ascent to Everest Base Camp (5,300 m). Aqueous and lipid fractions of plasma were separated and analysed using proton (1H)-nuclear magnetic resonance spectroscopy and direct infusion mass spectrometry, respectively. Bayesian robust hierarchical regression revealed decreasing isoleucine with ascent alongside increasing lactate and decreasing glucose, which may point towards increased glycolytic rate. Changes in the lipid profile with ascent included a decrease in triglycerides (48–50 carbons) associated with de novo lipogenesis, alongside increases in circulating levels of the most abundant free fatty acids (palmitic, linoleic and oleic acids). Together, this may be indicative of fat store mobilisation. This study provides the first broad metabolomic account of progressive exposure to environmental hypobaric hypoxia in healthy humans. Decreased isoleucine is of particular interest as a potential contributor to muscle catabolism observed with exposure to hypoxia at altitude. Substantial changes in lipid metabolism may represent important metabolic responses to sub-acute exposure to environmental hypoxia.

Hypoxia is a feature of many disease states where convective oxygen delivery is impaired, and is known to suppress oxidative metabolism. Acclimation to hypoxia thus requires metabolic remodelling, however hypoxia tolerance may be aided by dietary nitrate supplementation. Nitrate improves tissue oxygenation and has been shown to modulate skeletal muscle tissue metabolism via transcriptional changes, including through the activation of peroxisome proliferator-activated receptor alpha (PPARα), a master regulator of fat metabolism. Here we investigated whether nitrate supplementation protects skeletal muscle mitochondrial function in hypoxia and whether PPARα is required for this effect. Wild-type and PPARα knockout (PPARα−/−) mice were supplemented with sodium nitrate via the drinking water or sodium chloride as control, and exposed to environmental hypoxia (10% O2) or normoxia for 4 weeks. Hypoxia suppressed mitochondrial respiratory function in mouse soleus, an effect partially alleviated through nitrate supplementation, but occurring independently of PPARα. Specifically, hypoxia resulted in 26% lower mass specific fatty acid-supported LEAK respiration and 23% lower pyruvate-supported oxidative phosphorylation capacity. Hypoxia also resulted in 24% lower citrate synthase activity in mouse soleus, possibly indicating a loss of mitochondrial content. These changes were not seen, however, in hypoxic mice when supplemented with dietary nitrate, indicating a nitrate dependent preservation of mitochondrial function. Moreover, this was observed in both wild-type and PPARα−/− mice. Our results support the notion that nitrate supplementation can aid hypoxia tolerance and indicate that nitrate can exert effects independently of PPARα., Highlights • Hypoxic exposure suppresses mitochondrial respiration in mouse skeletal muscle. • Loss of citrate synthase activity suggests decreased mitochondrial content. • Dietary inorganic nitrate partially protects against hypoxia-induced changes. • Nitrate protects independently of peroxisome proliferator-activated receptor α.

Objectives: A rapid and early loss of skeletal muscle mass underlies the physical disability common amongst survivors of critical illness. However, skeletal muscle function depends not only on its quantity but its quality, which may be adversely affected. We set out to characterise the changes in macroscopic muscle echogenicity and fascial characteristics that occur early in critical illness, and to relate these to microscopic histologically defined myofibre necrosis and fascial pathology. Design and Setting: Prospective two center observational study. Patients: Thirty subjects comprising a subgroup of patients recruited to the Musculoskeletal Ultrasound in Critical Illness: Longitudinal Evaluation (MUSCLE) study. Measurements and Main Results: Comparisons were made between sequential Vastus Lateralis histological specimens and ultrasound assessment of Rectus Femoris echogenicity. Change in muscle echogenicity was greater in patients who developed muscle necrosis (n = 15) than in those who did not (8.2% [95% CI, –5.3 to 21.7] vs –15.0% [95% CI, –28.9 to –1.09]; p = 0.016). The area under receiver operator curve for ultrasound echogenicity’s prediction of myofiber necrosis was 0.74 (95% CI, 0.565 to 0.919; p = 0.024) increasing to 0.85 (95% CI, 0.703 to –0.995; p = 0.003) with the removal of those with potential iatrogenic muscle damage. Fasciitis was observed in 18 of 30 biopsies (60%). Conclusions: Myofiber necrosis and fascial inflammation can be detected noninvasively using ultrasound in the critically ill. Fasciitis precedes and frequently accompanies muscle necrosis. These findings may have functional implications for survivors of critical illness. (Crit Care Med 2015; 43:1603–1611)

Key Points The relationship between age and physiological function remains poorly defined and there are no physiological markers that can be used to reliably predict the age of an individual. This could be due to a variety of confounding genetic and lifestyle factors, and in particular to ill-defined and low levels of physical activity. This study assessed the relationship between age and a diverse range of physiological functions in a cohort of highly active older individuals (cyclists) aged 55–79 years in whom the effects of lifestyle factors would be ameliorated. Significant associations between age and function were observed for many functions. VO2 max was most closely associated with age, but even here the variance in age for any given level was high, precluding the clear identification of the age of any individual. The data suggest that the relationship between human ageing and physiological function is highly individualistic and modified by inactivity. Abstract Despite extensive research, the relationship between age and physiological function remains poorly characterised and there are currently no reliable markers of human ageing. This is probably due to a number of confounding factors, particularly in studies of a cross-sectional nature. These include inter-subject genetic variation, as well as inter-generational differences in nutrition, healthcare and insufficient levels of physical activity as well as other environmental factors. We have studied a cohort of highly and homogeneously active older male (n = 84) and female (n = 41) cyclists aged 55–79 years who it is proposed represent a model for the study of human ageing free from the majority of confounding factors, especially inactivity. The aim of the study was to identify physiological markers of ageing by assessing the relationship between function and age across a wide range of indices. Each participant underwent a detailed physiological profiling which included measures of cardiovascular, respiratory, neuromuscular, metabolic, endocrine and cognitive functions, bone strength, and health and well-being. Significant associations between age and function were observed for many functions. The maximal rate of oxygen consumption (VO2 max ) showed the closest association with age (r = −0.443 to −0.664; P

The rise in prevalence rates of Type 2 Diabetes among Indians is well recognized. The research focus has been primarily to understand the changes in insulin sensitivity and beta cell dysfunction among Indians with Type 2 Diabetes. However, no data are available on the role of peripheral tissue, in particular intramyocellular lipid (IMCL) content and its impact on glucose homeostasis among Indians with prediabetes. 28 male subjects (20–40 year) were studied. 13 with prediabetes (BMI ranging from 25.4 ± 2.9 kg/m2) and 15 controls (BMI ranging from 24.6 ± 2.8 kg/m2) were recruited. Body composition by dual energy X-ray absorptiometry (DXA), insulin sensitivity, insulin secretion rates were derived using the minimal model of C-peptide secretion and kinetics rates and skeletal muscle strength of the lower limb (quadriceps) was assessed using Isokinetic dynamometry. From muscle biopsy samples of the vastus lateralis, IMCL fat content (Oil red O staining) was determined. The prediabetes group were older compared to controls (P

Human evolution suggests that the default position for health is to be physically active. Inactivity, by contrast, has serious negative effects on health across the lifespan. Therefore, only in physically active people can the inherent aging process proceed unaffected by disuse complications. In such individuals, although the relationship between age and physiological function remains complex, function is generally superior with health, well being, and the aging process optimized.

BACKGROUND Cardiovascular reflexes that regulate blood pressure (BP) adapt during repeated exposure to +Gz acceleration separated by short (< 20 s) breaks, but whether this effect is preserved with longer intervals remains unknown. METHODS There were 17 subjects who completed 5 repeated gradual onset (0.1 G x s(-1)) runs (GOR1-5) to 60 degrees peripheral light loss (PLL) on a human centrifuge, separated by 2 min. Heart rate (HR) and BP were measured before and during each GOR and noninvasive estimation of cardiac output (CO) was used to calculate total peripheral resistance (TPR). RESULTS Mean resting (+/- SE) systolic BP (138 +/- 4 vs. 128 +/- 3 mmHg) and TPR (13.9 +/- 1.2 vs. 12.7 +/- 1.0 mmHg x L(-1) x min(-1)) were elevated after GOR1 and remained elevated thereafter. Compared with that before GOR1, resting HR was decreased (5-6 bpm) before GOR2-5. Resting CO decreased from 8.3 +/- 0.6 L x min(-1) before GOR1 to a nadir of 7.2 +/- 0.5 L x min(-1) before GOR4 and GOR5. The change in HR under increased +Gz decreased from +39 +/- 3 bpm during GOR1 to +31 +/- 3 bpm during GOR4 and GOR5, but the decrease in eye level BP under +Gz was unaffected. RGT did not change across the five GORs. CONCLUSIONS Increased resting BP and TPR following a single +Gz exposure suggest alterations in the cardiovascular system expected to confer improved tolerance during subsequent exposures. However, these changes were insufficient to improve +Gz tolerance measured during repeated GORs separated by 2 min.

The myogenic behaviour of primary human muscle precursor cells (MPCs) obtained from young (aged 20-25 years) and elderly people (aged 67-82 years) was studied in culture. Cells were compared in terms of proliferation, DNA damage, time course and extent of myogenic marker expression during differentiation, fusion, size of the formed myotubes, secretion of the myogenic regulatory cytokine TGF-β1 and sensitivity to TGF-β1 treatment. No differences were observed between cells obtained from the young and elderly people. The cell populations were expanded in culture until replicative senescence. Cultures that maintained their initial proportion of myogenic cells (desmin positive) with passaging (n = 5) were studied and compared with cells from the same individuals in the non-senescent state. The senescent cells exhibited a greater number of cells with DNA damage (γ-H2AX positive), showed impaired expression of markers of differentiation, fused less well, formed smaller myotubes and secreted more TGF-β. The data strongly suggest that MPCs from young and elderly people have similar myogenic behaviour.

Objective: Functional capacity is commonly impaired after critical illness. We sought to clarify the relationship between objective measures of physical activity, self-reported measures of health-related quality of life, and clinician reported global functioning capacity (frailty) in such patients, as well as the impact of prior chronic disease status on these functional outcomes. Design: Prospective outcome study of critical illness survivors. Setting: Community-based follow-up. Patients: Participants of the Musculoskeletal Ultrasound Study in Critical Care: Longitudinal Evaluation Study (NCT01106300), invasively ventilated for more than 48 hours and on the ICU greater than 7 days. Interventions: None. Measurements and Main Results: Physical activity levels (health-related quality of life [36-item short-form health survey] and daily step counts [accelerometry]) were compared to norm-based or healthy control scores, respectively. Controls for frailty (Clinical Frailty Score) were non-morbid, age- and gender-matched to survivors. Ninety-one patients were recruited on ICU admission: 41 were contacted for post-discharge assessment, and data were collected from 30 (14 female; mean age, 55.3 yr [95% CI, 48.3-62.3]; mean post-discharge, 576 d [95% CI, 539-614]). Patients' mean daily step count (5,803; 95% CI, 4,792-6,813) was lower than that in controls (11,735; 95% CI, 10,928-12,542; p < 0.001), and lower in those with preexisting chronic disease than without (2,989 [95% CI, 776-5,201] vs 7,737 [95% CI, 4,907-10,567]; p = 0.013). Physical activity measures (accelerometry, health-related quality of life, and frailty) demonstrated good construct validity across all three tools. Step variability (from SD) was highly correlated with daily steps (r2 = 0.67; p < 0.01) demonstrating a potential boundary constraint. Conclusions: Subjective and objective measures of physical activity are all informative in ICU survivors. They are all reduced 18 months post-discharge in ICU survivors, and worse in those with pre-admission chronic disease states. Investigating interventions to improve functional capacity in ICU survivors will require stratification based on the presence of premorbidity.

The accurate measurement of the morphological characteristics of cells with nonuniform conformations presents difficulties. We report here a straightforward method using immunofluorescent staining and the commercially available imaging program Adobe Photoshop, which allows objective and precise information to be gathered on irregularly shaped cells. We have applied this measurement technique to the analysis of human muscle cells and their immunologically marked intracellular constituents, as these cells are prone to adopting a highly branched phenotype in culture. Use of this method can be used to overcome many of the long-standing limitations of conventional approaches for quantifying muscle cell size in vitro. In addition, wider applications of Photoshop as a quantitative and semiquantitative tool in immunocytochemistry are explored.

We are an ageing society, with falling birth rates and increasing life expectancy. However healthy life span is not keeping pace and on average older adults can expect to be unwell for the last decade of life. Many factors influence both lifespan and healthspan but in humans one of the key factors is likely to be increasing physical inactivity. To separate out those elements of the ageing phenotype that are due to inactivity from those which are intrinsic to the ageing process, we recruited 125 adults aged 55-79 who had maintained a high level of physical activity through their adult lives. We compared these with age matched healthy older adults who were not involved in regular physical activity and healthy young subjects. The subjects were assessed for key features known to change with ageing including sarcopenia, reduced bone mineral density, adiposity, cardiovascular and lung function as well as markers of immune ageing. We have already reported the physiological data which revealed that many features of ageing including lean body mass, adiposity and muscle strength did not change with age in the physical active group, though other effects were seen such as a decline in lung capacity (FEV1) and maximal heart rate. Here we report that a comparison of immune phenotype in the exercising and non-exercising groups showed that thymic output was significantly reduced in the inactive group compared to both the young subjects (p

Impaired physical function and reduced physical activity are common findings in intensive care unit (ICU) survivors. More importantly, reduced muscle strength during critical illness is an independent predictor of survival. Skeletal muscle wasting as a direct consequence of critical illness has been suggested as the cause. However, data on the physiological processes regulating muscle mass, and function, in these critically ill patients are limited as this is not only a technically challenging research area, but also the heterogeneity of the patient group adds complexity to the interpretation of results. Despite this, clinical and research interest in this area is growing. This article highlights the issues involved in measurement of muscle function and mass in critically ill patients and the physiological complexities involved in studying these patients. Although the data are limited, this article reviews the animal and healthy human data providing a rational approach to the potential pathophysiological mechanisms involved in muscle mass regulation in critically ill patients, including the established muscle wasting ‘risk factors’ such as ageing, immobility and systemic inflammation, all of which are common findings in the general critical care population.

Using a human primary muscle cell culture model the behaviour of myoblasts (satellite cells) cultured in human serum obtained from either young or elderly individuals was studied. Serum was obtained from a total of 13 young (7 males and 6 females aged, 23-36 years) and 9 elderly (4 males and 5 females aged 69-84 years) subjects and used in a number of experiments. Myoblasts were extracted from human muscle biopsy samples taken from the vastus lateralis. In the first experiment myoblasts were isolated immediately after extraction from the biopsy in media containing human sera to examine its effects on the onset and progression of Ki67 and desmin expression. No effect of the age of the serum was observed at 3, 5 or 7 days of culture. In addition, cells were studied that had been expanded initially in optimum myoblast growth medium (GM, containing foetal calf serum and additional growth factors) prior to culture in medium containing 15% human serum. The proportion of proliferating muscle cells coexpressing desmin and Ki67 antigens after 46 h was again similar in the young and old serum conditions. Culturing these myoblasts in media containing 2% human serum to study their fusion and differentiation also resulted in no difference between young and old serum conditions in terms of the percentage of nuclei inside myosin heavy chain positive myotubes. Despite the variability of different samples of myoblasts, the age of the serum donor has no effect on the expression of any measured index.

Electrical stimulation (ES) improves muscle properties after spinal cord injury (SCI), but cycling power output (PO) remains low. We investigated the effect of endurance and strength ES training on these parameters. Assessments of quadriceps strength and fatigue resistance, cycling PO, and muscle biopsies were made in four well-trained SCI subjects (three cyclists and one rower) before and after additional weight training in the cyclists and once in the rower. Weight training improved muscle strength, but cycling PO was low in all subjects. There was no effect of training type on biopsy data. Biopsies showed non-specific signs of pathology, predominance of type IIa fibers, and uniform metabolic activity. Oxidative activity was low, as were capillary:fiber ratios in the cyclists. Cycling PO is limited by factors other than muscle strength. Future ES training studies should attempt to improve muscle oxidative capacity to optimize the potential benefits of ES exercise.

Background and aims: Chair rise performance, which is simple to assess in a home or clinic setting, has been used as a method of predicting leg power deficit in older adults. More recently, chair rise performance has been assessed in younger populations as a baseline for assessment of subsequent age-related declines in function and power. However, as rising from a chair repeatedly not only requires lower limb strength and power but also good balance and coordination, it may not be purely a measure of leg power especially among these younger, well functioning groups who are yet to experience agerelated declines and deficits in function. The aim of this study was to assess whether chair rise performance can be considered as a predictor of leg power, and hence of deficits in this, in men and women in mid-life. We assessed the relationship of chair rise performance with leg extensor power (LEP), measured using the Nottingham Power Rig (NPR), and with standing balance performance. Methods: LEP was measured in a clinic setting in a sub-sample of 81 men and 93 women from the MRC National Survey of Health and Development, a nationally representative cohort born in Britain in 1946. The time taken to rise from a chair 10 times and standing balance time were assessed during home visits at the same age. Results: Increasing LEP was associated with better chair rise performance among those who completed 10 chair rises in ≥15 seconds, after adjustment for body size (p=0.008). Better standing balance performance was associated with better chair rise performance in men, but not women. Conclusions: That LEP and standing balance are both related to chair rise time in men suggests that chair rise time should not be thought of purely as a proxy measure of leg power in middle-aged populations. This has implications for longitudinal studies which want to study age-related decline in chair rise performance.

In this study, results are reported from the analyses of vastus lateralis muscle biopsy samples obtained from a subset (n = 90) of 125 previously phenotyped, highly active male and female cyclists aged 55-79 years in regard to age. We then subsequently attempted to uncover associations between the findings in muscle and in vivo physiological functions. Muscle fibre type and composition (ATPase histochemistry), size (morphometry), capillary density (immunohistochemistry) and mitochondrial protein content (Western blot) in relation to age were determined in the biopsy specimens. Aside from an age-related change in capillary density in males (r = -.299; p = .02), no other parameter measured in the muscle samples showed an association with age. However, in males type I fibres and capillarity (p < .05) were significantly associated with training volume, maximal oxygen uptake, oxygen uptake kinetics and ventilatory threshold. In females, the only association observed was between capillarity and training volume (p < .05). In males, both type II fibre proportion and area (p < .05) were associated with peak power during sprint cycling and with maximal rate of torque development during a maximal voluntary isometric contraction. Mitochondrial protein content was not associated with any cardiorespiratory parameter in either males or females (p > .05). We conclude in this highly active cohort, selected to mitigate most of the effects of inactivity, that there is little evidence of age-related changes in the properties of VL muscle across the age range studied. By contrast, some of these muscle characteristics were correlated with in vivo physiological indices.

Summary It is widely accepted that aging is accompanied by remodelling of the immune system including thymic atrophy and increased frequency of senescent T cells, leading to immune compromise. However, physical activity, which influences immunity but declines dramatically with age, is not considered in this literature. We assessed immune profiles in 125 adults (55–79 years) who had maintained a high level of physical activity (cycling) for much of their adult lives, 75 age‐matched older adults and 55 young adults not involved in regular exercise. The frequency of naïve T cells and recent thymic emigrants (RTE) were both higher in cyclists compared with inactive elders, and RTE frequency in cyclists was no different to young adults. Compared with their less active counterparts, the cyclists had significantly higher serum levels of the thymoprotective cytokine IL‐7 and lower IL‐6, which promotes thymic atrophy. Cyclists also showed additional evidence of reduced immunesenescence, namely lower Th17 polarization and higher B regulatory cell frequency than inactive elders. Physical activity did not protect against all aspects of immunesenescence: CD28−ve CD57+ve senescent CD8 T‐cell frequency did not differ between cyclists and inactive elders. We conclude that many features of immunesenescence may be driven by reduced physical activity with age.

In skeletal muscle there is good evidence to suggest that locally produced insulin-like growth factor-1 (IGF-I), rather than circulating IGF-I, is important in regard to muscle mass maintenance, repair and hypertrophy. This "mature" IGF-I comprises exons 3 and 4 of the IGF-I gene, but during processing the full length gene (which contains six exons) is subject to a process of alternative splicing. As a result smaller peptides (E peptides) are believed to be cleaved from the mature IGF-I peptide during processing of the prohormone and the likelihood is that they have different biological roles. In human skeletal muscle three transcripts encoding for these splice variants (IGF-IEa, IGF-IEb and IGF-IEc, also known as MGF) can be identified. When studied at the mRNA level these three transcripts are known to be upregulated in the muscles of elderly people following high resistance exercise, albeit with different time courses. However, compared with mature IGF-I relatively little is known about the mechanism of action of the different E peptides.