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Recent studies have identified skeletal muscle as a tissue compartment where nitrate and nitrite can be stored and utilized to potentially maintain nitric oxide (NO) homeostasis. Given its capacity to reduce nitrate and nitrite, the molybdopterin-containing enzyme, xanthine oxidoreductase (XOR) has been suggested as a key enzyme within skeletal muscle which catalytically reduces these N-oxides; however, there remains limited insight into the role of XOR in this process as well as how different conditions (e.g. health vs disease and rest vs exercise) may determine when and where, within skeletal muscle, XOR could serve as a significant source of NO. A key factor that determines the extent by which XOR may or may not contribute to NO generation in a biologically relevant manner is the biochemical landscape (e.g. oxygen tension, pH, isoform of XOR (XDH vs. XO) and substrate levels of the microenvironment in normal versus stressed skeletal muscle. As such, a critical focus of this review is the evaluation of the biochemical and physiologic data supporting the role of XOR within skeletal muscle for supplying nitrite and/or NO from endogenous and exogenous sources during pathophysiologic conditions and/or exercise stress.

Childhood sport participation is associated with physical, social, and mental health benefits, which are more likely to be realized if the sport environment is safe. However, our understanding of children’s experience of psychological, physical, and sexual violence in community sport in Australia is limited. The aims of this study were to provide preliminary evidence on the extent of experiences of violence during childhood participation in Australian community sport and to identify common perpetrators of and risk factors for violence. The Violence Towards Athletes Questionnaire (VTAQ) was administered online to a convenience sample of Australian adults (>18 years), retrospectively reporting experiences of violence during childhood community sport. Frequencies of experience of violence were calculated and Chi-square tests were conducted to determine differences between genders. In total, there were 886 respondents included in the analysis. Most survey respondents were women (63%) and about a third were men (35%). About 82% of respondents experienced violence in sport as a child. Psychological violence was most prevalent (76%), followed by physical (66%) and sexual (38%) violence. Peers perpetrated the highest rates of psychological violence (69%), and the rates of physical and psychological violence by coaches (both >50%) were also high. Age, sexual orientation, disability, and hours of weekly sport participation as a child were all associated with childhood experience of violence in sport. The rates of interpersonal violence against children in sport were high. This novel data on perpetrators of the violence and the risk factors for experiencing violence provides further context to inform safeguarding strategies in sport. A national prevalence study is recommended to advance our understanding of the childhood experiences of violence in Australian sport.

Heart failure (HF) results in a myriad of central and peripheral abnormalities that impair the ability to sustain skeletal muscle contractions and, therefore, limit tolerance to exercise. Chief among these abnormalities is the lowered maximal oxygen uptake, which is brought about by reduced cardiac output and exacerbated by O2delivery-utilization mismatch within the active skeletal muscle. Impaired nitric oxide (NO) bioavailability is considered to play a vital role in the vascular dysfunction of both reduced and preserved ejection fraction HF (HFrEF and HFpEF, respectively), leading to the pursuit of therapies aimed at restoring NO levels in these patient populations. Considering the complementary role of the nitrate-nitrite-NO pathway in the regulation of enzymatic NO signaling, this review explores the potential utility of inorganic nitrate interventions to increase NO bioavailability in the HFrEF and HFpEF patient population. Although many preclinical investigations have suggested that enhanced reduction of nitrite to NO in low Po2and pH environments may make a nitrate-based therapy especially efficacious in patients with HF, inconsistent results have been found thus far in clinical settings. This brief review provides a summary of the effectiveness (or lack thereof) of inorganic nitrate interventions on exercise tolerance in patients with HFrEF and HFpEF. Focus is also given to practical considerations and current gaps in the literature to facilitate the development of effective nitrate-based interventions to improve exercise tolerance in patients with HF.

BACKGROUND The demand for orthopaedic specialist consultation for patients with osteoarthritis (OA) in public hospitals is large and continues to grow. Lengthy wait times are increasingly affecting patients from low socioeconomic and culturally and linguistically diverse (CALD) backgrounds who are more likely to rely on public health care. OBJECTIVE The aim of this study was to co-design a digital health intervention for patients with OA who are waiting for an orthopaedic specialist consultation at a public health service, which is located in local government areas (LGAs) of identified social and economic disadvantage. METHODS The stakeholders involved in the co-design process included the research team, end-users (patients), clinicians, academic experts, senior hospital staff and a research, design and development agency. The iterative co-design process comprised of several key phases, which included the collation and refinement of evidence-based information by the research team with assistance from academic experts. Structured interviews with 16 clinicians (sex: 10 female and six male) and 11 end-users (mean ± SD, age: 64.3 ± 7.2, sex: seven female and four male) of 1-hour duration were completed to understand the needs of the intervention. Weekly workshops were held with key stakeholders throughout the development. A different cohort of 15 end-users examined the feasibility of the study during a 2-week testing period (age: 61.5 ± 9.7, sex: 12 female and three male). The system usability scale (SUS) was utilized as the primary measure of the feasibility of the intervention. RESULTS Seven content modules were developed which were refined over several iterative rounds. Key themes highlighted in the clinician and end-user interviews were the diverse characteristics of patients, the hierarchical structure with which patients view health practitioners, the importance of delivering information in multiple formats (written, audio and visual) and access to patient-centered information as early as possible in the healthcare journey. All content was translated to Vietnamese, the most widely spoken language following English in the LGAs included in this study. Patients with hip and knee OA from diverse CALD backgrounds tested its feasibility. A mean score of 82.7 ± 16 was recorded for the SUS placing it in the excellent category for usability. CONCLUSIONS Through the co-design process, we developed an evidence-based, holistic and patient-centered digital health intervention. The intervention has been specifically designed to be used by patients from diverse backgrounds, including those with low health, digital and written literacy levels. The effectiveness of the intervention for improving the physical and mental health of patients will be determined by a high-quality randomized controlled trial.

Initiatives to safeguard athletes from interpersonal violence (IV) are rapidly growing. In Belgium, knowledge on the magnitude of IV in sport is based on one retrospective prevalence study from 2016 (n = 2.043 adults), involving those who had participated in organized sport for up to 18 years. Data on victimization rates in current youth sport populations are lacking. This study aimed to investigate the magnitude of IV in a sample of 769 athletes (aged between 13 and 21), using the Violence Towards Athletes Questionnaire (VTAQ). All types of IV were prevalent in this sample, ranging from 27% (sexual violence) to 79% (psychological violence and neglect). Boys reported significantly more physical violence, while girls reported significantly more sexual violence. IV perpetrated by peer athletes was reported to the same degree as IV perpetrated by a coach (70%), while IV perpetrated by a parent in the context of sport was somewhat less common, but still prevalent (48%). These findings, including factors associated with elevated exposure rates, can serve as a baseline measurement to monitor and evaluate current and future safeguarding interventions in Belgian sport.

Background Osteoarthritis (OA) is a chronic, progressive condition that can be effectively managed via conservative treatments including exercise, weight management and education. Offering these treatments contemporaneously and digitally may increase adherence and engagement due to the flexibility and cost-effectiveness of digital program delivery. The objective of this review was to summarise the characteristics of current digital self-management interventions for individuals with OA and synthesise adherence and attrition outcomes. Methods Electronic databases were searched for randomised controlled trials utilising digital self-management interventions in individuals with OA. Two reviewers independently screened the search results and extracted data relating to study characteristics, intervention characteristics, and adherence and dropout rates. Results Eleven studies were included in this review. Intervention length ranged from 6 weeks to 9 months. All interventions were designed for individuals with OA and mostwere multi-component and were constructed around physical activity. The reporting of intervention adherence varied greatly between studies and limited the ability to form conclusions regarding the impact of intervention characteristics. However, of the seven studies that quantified adherence, six reported adherence > 70%. Seven of the included studies reported attrition rates Conclusions Holistic digital interventions designed for a targeted condition are a promising approach for promoting high adherence and reducing attrition. Future studies should explore how adherence of digital interventions compares to face-to-face interventions and determine potential influencers of adherence.

Bone and muscle are closely linked mechanically and biochemically. Bone hormones secreted during bone remodeling might be linked to muscle mass and strength maintenance. Exercise elicits high mechanical strain and is essential for bone health. However, the relationship between commonly used bone turnover markers (BTMs) and muscle function in community dwelling older adults remains unclear. It is also unknown how acute exercise with differing mechanical strain may affect BTMs, and whether baseline muscle function alters BTM responses differently. We tested the hypothesis that BTMs are associated with muscle function, and that acute exercise could change the circulating levels of BTMs. Thirty-five older adults (25 females/10 males, 72.8 ± 6.0 years) participated. Baseline assessments included body composition (DXA), handgrip strength and a physical performance test (PPT) (gait speed, timed-up-and-go [TUG], stair ascent/descent). Leg muscle quality (LMQ) and stair climb power (SCP) were calculated. Participants performed (randomized) 30 min aerobic (AE) (cycling 70%HRPeak) and resistance (RE) (leg press 70%RM, jumping) exercise. Serum β-isomerized C-terminal telopeptides (β-CTX), procollagen of type I propeptide (P1NP), total osteocalcin (t)OC and ucOC were assessed at baseline and post-exercise. Data were analyzed using linear mixed models and simple regressions, adjusted for sex. At baseline, higher muscle strength (LMQ, handgrip) was related to higher P1NP, higher SCP was related to higher P1NP and β-CTX, and better physical performance (lower PPT) related to higher P1NP and β-CTX (p < 0.05). Exercise, regardless of mode, decreased β-CTX and tOC (all p < 0.05), while P1NP and ucOC remained unaltered. Higher baseline handgrip strength, SCP and LMQ was associated with lower post-exercise β-CTX responses, and poorer baseline mobility (increased TUG time) was associated with higher post-exercise β-CTX. Independently of exercise mode, acute exercise decreased β-CTX and tOC. Our data suggest that in older adults at baseline, increased BTM levels were linked to better muscle function. Altogether, our data strengthens the evidence for bone-muscle interaction, however, mechanisms behind this specific component of bone-muscle crostalk remain unclear.

Context Osteoglycin (OGN) is a proteoglycan released from bone and muscle which has been associated with markers of metabolic health. However, it is not clear whether the levels of circulating OGN change throughout the adult lifespan or if they are associated with clinical metabolic markers or fitness. Objective We aimed to identify the levels of circulating OGN across the lifespan and to further explore the relationship between OGN and aerobic capacity as well as OGN’s association with glucose and HOMA-IR. Methods 107 individuals (46 males and 61 females) aged 21-87 years were included in the study. Serum OGN levels, aerobic capacity (VO2peak), glucose, and homeostatic model assessment for insulin resistance (HOMA-IR) were assessed. T-tests were used to compare participant characteristics between sexes. Regression analyses were performed to assess the relationship between OGN and age, and OGN and fitness and metabolic markers. Results OGN displayed a nonlinear, weak “U-shaped” relationship with age across both sexes. Men had higher levels of OGN than women across the lifespan (β = 0.23, P = .03). Age and sex explained 16% of the variance in OGN (adjusted R2 = 0.16; P < .001). Higher OGN was associated with higher VO2peak (β = 0.02, P = .001); however, those aged 50. A higher OGN level was associated with a higher circulating glucose level (β = 0.17, P < .01). No association was observed between OGN and HOMA-IR. Conclusion OGN was characterized by a U-shaped curve across the lifespan which was similar between sexes. Those with a higher aerobic capacity or higher glucose concentration had higher OGN levels. Our data suggest an association between OGN and aerobic fitness and glucose regulation. Future studies should focus on exploring the potential of OGN as a biomarker for chronic disease.

A reduction in aerobic capacity and the shortening of telomeres are hallmarks of the ageing process. We examined whether a lower aerobic capacity is associated with shorter TL in skeletal muscle and/or leukocytes, across a wide age range of individuals. We also tested whether TL in human skeletal muscle (MTL) correlates with TL in leukocytes (LTL). Eighty-two recreationally active, healthy men from the Gene SMART cohort (31.4±8.2 years; body mass index (BMI)=25.3±3.3kg/m2), and 11 community dwelling older men (74.2±7.5years-old; BMI=28.7±2.8kg/m2) participated in the study. Leukocytes and skeletal muscle samples were collected at rest. Relative telomere length (T/S ratio) was measured by RT-PCR. Associations between TL, aerobic capacity (VO2 peak and peak power) and age were assessed with robust linear models. Older age was associated with shorter LTL (45% variance explained, P

Exercise training beneficially moderates the effects of vascular aging. This study compared the efficacy of Peripheral Remodeling through Intermittent Muscular Exercise (PRIME), a novel training regimen, versus aerobic training on hemodynamic profiles in participants ≥70 years at risk for losing functional independence. Seventy-five participants (52 females, age: 76 ± 5 years) were assessed for hemodynamic and vascular function at baseline, after 4 weeks of either PRIME or aerobic training (Phase 1) and again after a further 8 weeks of aerobic and resistance training (Phase 2). Data were analyzed using 2 × 2 repeated-measures analysis of variance models on the change in each dependent variable. PRIME demonstrated reductions in brachial and aortic mean arterial pressure and diastolic blood pressure (p

Since the beginning of time people explored and developed new technologies to make their activities of daily living less labour intense, more efficient and, consequently, more sedentary. In addition, technological advances in medicine throughout history have led to a substantial increase in life expectancy. However, the combination of increased sedentary behaviour and increased life-expectancy resulted in a sharp increase in overweight and obesity related chronic conditions and illness. Although people may live longer, they are doing so with poorer physical function and a reduced quality of life. In this review we explore how technological advances have influenced people's sedentary behaviour and, through the lens of the affective-reflective theory (ART), we propose a means by which technology could be repurposed to encourage greater engagement in physical activity.

The loss of muscle mass, strength and function, known as sarcopenia, is common in older adults, and is associated with falls, fractures, cardiometabolic diseases, and lower quality of life. Sarcopenia can also occur secondarily to chronic diseases. Recently, sarcopenia was recognized as a disease with an International Classification of Disease (ICD) code, yet, at least five definitions for its clinical identification exist. Most definitions include three themes: low muscle mass, strength and physical performance. However, the definitions vary by the number of themes needed to diagnose sarcopenia and, within each theme various parameters and cut-off levels exist. The lack of consensus on what constitutes a diagnosis can create confusion and hesitation in sarcopenia diagnosis. Currently, no pharmacological treatment exists for sarcopenia. Resistance training (RT) is safe and effective to improve muscle mass, strength and physical performance in older adults and clinical populations. Based on current guidelines, whether an individual is defined as "sarcopenic", or not, does not change the way RT is prescribed. Here, we present evidence and the inconsistencies in sarcopenia definitions and recommend that focus should be on optimizing ways to prescribe RT and increase long-term adherence, rather than on slight modifications to sarcopenia definitions.

Introduction: Peak oxygen utilisation (VO 2 ) and ventilatory efficiency (VE/VCO 2 slope) provide strong prognostic information in symptomatic heart failure (HF). Transition from subclinical to symptomatic HF is poorly understood. Cardiopulmonary exercise testing (CPET) in subclinical HF may advance risk profiling. Hypothesis: HF risk factors are associated with metabolic and ventilatory abnormalities that may serve as risk markers. Methods: Sedentary subjects (n=81; 67 (66-72) years; 65% female; BMI 29.9[26.6-33.9] kg/m 2 ) with ≥1 HF risk factors (Stage A HF, SAHF) without pulmonary disease and healthy sedentary subjects (controls, n=21; 70 (67-73) years; 52% female; BMI 25.1 [24-25.9] kg/m 2 ) underwent treadmill CPET to determine peak VO 2 , ventilatory threshold (VT, V-slope method) and VE/VCO 2 slope (linear regression). Global longitudinal strain≤16%, diastolic dysfunction or left ventricular hypertrophy defined subclinical left ventricular dysfunction (LVD). Results: LVD was present in 41 (51%) with SAHF. CPET parameters did not differ by presence of LVD. There were no differences in peak RER or VT (% peak VO2) between controls and SAHF. VO 2 peak was higher in controls vs. SAHF (22.1±4.6 vs. 19.9±4.6ml/kg/min, p=0.047). VE/VCO 2 slope was markedly steeper in SAHF vs. controls (40.2±6.2 vs. 29.3±6.1, p2 slope was >34 (prognostic in symptomatic HF) in 83% vs. 19% for SAHF vs. controls (p2 0.16) of VE/VCO 2 slope (SBP and heart rate reserve were not). BMI was not associated with increment in respiratory rate or tidal volume (β0.18(-0.07-0.42) and β3.9 (-10.8-18.7)). Conclusions: Cardiorespiratory exercise parameters do not differ in SAHF by presence of LVD. Ventilatory inefficiency is pronounced in SAHF compared with healthy controls suggesting it may be a risk marker, but prognostic significance is unknown.

Background Subclinical heart failure (HF) is divided into Stage A and B (SAHF and SBHF) depending on structural or functional cardiac abnormalities. However, risk of HF progression is not solely dependent on echocardiographic abnormalities. Data on oxygen consumption (VO2) and other prognostic cardiopulmonary exercise test (CPET) markers in subclinical HF, particularly in the elderly, is lacking. VO2 may refine risk prediction and provide pathological insight in subclinical HF. Methods Asymptomatic individuals were recruited through primary care if they were ≥65 years with ≥1 non-ischaemic risk factor for HF. Clinical evaluation determined risk profile, biometrics and NT-proBNP. Treadmill CPET was undertaken with a modified Bruce protocol. Low V02 was defined as ≤20th percentile of age and gender specific VO2 in healthy individuals. SBHF defined as systolic (global longitudinal strain, GLS ≤16%), diastolic (E/e' ≥15, E/e' >10 with left atrial enlargement or impaired relaxation with other changes or left ventricular (LV) hypertrophy (LV mass index >95 g/m2 in women or >115 g/m2 in men). Results Of the 91 included individuals (age 71±4 years, 53% female), 46 (51%) had SBHF, average NT-proBNP was 60pg/ml (26–99mg/ml) and did not differ by HF stage (59 [26–85] pg/ml vs. 60 [30–99] pg/ml for Stage A vs. B respectively, p=0.94). Average peak VO2 was 19.8 (16–22.6) ml/kg/min and was low in 71 (78%). VO2 did not differ by HF stage (19.9 [17.7–22.4] ml/kg/min vs. 19.7 [16–22.8] ml/kg/min for SAHF vs. SBHF respectively, p=0.62). NT-proBNP was significantly higher in those with abnormal VO2 (66 [34–110] pg/ml vs 31 [20–70] pg/ml, p=0.016). Within each HF stage, low VO2 was associated with higher NT-proBNP (Figure). Of those with NT-proBNP >100pg/ml, 95% (22/23) had low VO2 compared with 72% of those ≤100pg/ml, p=0.02 (non-signifcant for 125pg/ml cut-off). No associations were found between SBHF or individual echo abnormalities and VO2. In logistic regression analysis NT-proBNP was a significant univariable predictor of low VO2 and remained significant after adjustment for other significant univariables (BMI) (OR 1.02 [95% CI 1.0001–1.03], p=0.048). Conclusion Low VO2 identifies a high-risk cardiac phenotype within subclinical HF stages, but is not necessarily associated with LV dysfunction. Levels of NT-proBNP beneath the cut-off used for HF exclusion may assist risk stratification in this population. NT-proBNP by VO2 in subclinical HF Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Dr E Potter is supported by a PhD Scholarship from Monash University, Melbourne, Australia

Background: Evidence suggests that lower serum undercarboxylated osteocalcin (ucOC) may be negatively associated with cardiometabolic health. We investigated whether individuals with a suppression of ucOC following an increase in dietary vitamin K1 exhibit a relative worsening of cardiometabolic risk factors. Materials and Methods: Men (n = 20) and women (n = 10) aged 62 ± 10 years participated in a randomized, controlled, crossover study. The primary analysis involved using data obtained from participants following a high vitamin K1 diet (HK; 4-week intervention of increased leafy green vegetable intake). High and low responders were defined based on the median percent reduction (30%) in ucOC following the HK diet. Blood pressure (resting and 24 h), arterial stiffness, plasma glucose, lipid concentrations, and serum OC forms were assessed. Results: Following the HK diet, ucOC and ucOC/tOC were suppressed more (p < 0.01) in high responders (41 and 29%) versus low responders (12 and 10%). The reduction in ucOC and ucOC/tOC was not associated with changes in blood pressure, arterial stiffness, plasma glucose, or lipid concentrations in the high responders (p > 0.05). Discussion/Conclusion: Suppression of ucOC via consumption of leafy green vegetables has no negative effects on cardiometabolic health, perhaps, in part, because of cross-talk mechanisms.

Chronic underperfusion of the skeletal muscle tissues is a contributor to a decrease in exercise capacity in patients with heart failure with reduced ejection fraction (HFrEF). This underperfusion is due, at least in part, to impaired nitric oxide (NO) bioavailability. Oral inorganic nitrate supplementation increases NO bioavailability and may be used to improve exercise capacity, vascular function, and mitochondrial respiration. Sixteen patients with HFrEF (fifteen men, 63 ± 4 yr, body mass index: 31.8 ± 2.1 kg/m2) participated in a randomized, double-blind, crossover design study. Following consumption of either nitrate-rich beetroot juice (16 mmol nitrate/day) or a nitrate-depleted placebo for 5 days, participants completed separate visits for assessment of exercise capacity, endothelial function, and muscle mitochondrial respiration. Participants then had a 2-wk washout before completion of the same protocol with the other intervention. Statistical significance was set a priori at P < 0.05, and between-treatment differences were analyzed via paired t test analysis. Following nitrate supplementation, both plasma nitrate and nitrite increased (933%, P < 0.001 and 94%, P < 0.05, respectively). No differences were observed for peak oxygen consumption (nitrate: 18.5 ± 1.4 mL·kg−1·min−1, placebo: 19.3 ± 1.4 mL·kg−1·min−1; P = 0.13) or time to exhaustion (nitrate: 1,165 ± 92 s, placebo: 1,207 ± 96 s; P = 0.16) following supplementation. There were no differences between interventions for measures of vascular function, mitochondrial respiratory function, or protein expression (all P > 0.05). Inorganic nitrate supplementation did not improve exercise capacity and skeletal muscle mitochondrial respiratory function in HFrEF. Future studies should explore alternative interventions to improve peripheral muscle tissue function in HFrEF.

Background There are conflicting reports on the association of undercarboxylated osteocalcin (ucOC) in cardiovascular disease development, including endothelial function and hypertension. We tested whether ucOC is related to blood pressure and endothelial function in older adults, and if ucOC directly affects endothelial-mediated vasodilation in the carotid artery of rabbits. Methods In older adults, ucOC, blood pressure, pulse wave velocity (PWV) and brachial artery flow-mediated dilation (BAFMD) were measured (n = 38, 26 post-menopausal women and 12 men, mean age 73 ± 0.96). The vasoactivity of the carotid artery was assessed in male New Zealand White rabbits following a four-week normal or atherogenic diet using perfusion myography. An ucOC dose response curve (0.3–45 ng/ml) was generated following incubation of the arteries for 2-hours in either normal or high glucose conditions. Results ucOC levels were higher in normotensive older adults compared to those with stage 2 hypertension (p < 0.05), particularly in women (p < 0.01). In all participants, higher ucOC was associated with lower PWV (p < 0.05), but not BAFMD (p > 0.05). In rabbits, ucOC at any dose did not alter vasoactivity of the carotid artery, either following a normal or an atherogenic diet (p > 0.05). Conclusion Increased ucOC is associated with lower blood pressure and increased arterial stiffness, particularly in post-menopausal women. However, ucOC administration has no direct short-term effect on endothelial function in rabbit arteries. Future studies should explore whether treatment with ucOC, in vivo, has direct or indirect effects on blood vessel function.

Background Bone and muscle are closely linked anatomically, biochemically, and metabolically. Acute exercise affects both bone and muscle, implying a crosstalk between the two systems. However, how these two systems communicate is still largely unknown. We will explore the role of undercarboxylated osteocalcin (ucOC) in this crosstalk. ucOC is involved in glucose metabolism and has a potential role in muscle maintenance and metabolism. Objective The proposed trial will determine if circulating ucOC levels in older adults at baseline and following acute exercise are associated with parameters of muscle function and if the ucOC response to exercise varies between older adults with low muscle quality and those with normal or high muscle quality. Methods A total of 54 men and women aged 60 years or older with no history of diabetes and warfarin and vitamin K use will be recruited. Screening tests will be performed, including those for functional, anthropometric, and clinical presentation. On the basis of muscle quality, a combined equation of lean mass (leg appendicular skeletal muscle mass in kg) and strength (leg press; one-repetition maximum), participants will be stratified into a high or low muscle function group and randomized into the controlled crossover acute intervention. Three visits will be performed approximately 7 days apart, and acute aerobic exercise, acute resistance exercise, and a control session (rest) will be completed in any order. Our primary outcome for this study is the effect of acute exercise on ucOC in older adults with low muscle function and those with high muscle function. Results The trial is active and ongoing. Recruitment began in February 2018, and 38 participants have completed the study as of May 26, 2019. Conclusions This study will provide novel insights into bone and muscle crosstalk in older adults, potentially identifying new clinical biomarkers and mechanistic targets for drug treatments for sarcopenia and other related musculoskeletal conditions. Trial Registration Australia New Zealand Clinical Trials Registry ACTRN12618001756213; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375925. International Registered Report Identifier (IRRID) DERR1-10.2196/18777

Nitric Oxide (NO) bioavailability is essential for vascular health. Dietary supplementation with inorganic nitrate, which is abundant in vegetables and roots, has been identified as an effective means of increasing vascular NO bioavailability. Recent studies have shown a reduction in resting blood pressures in both normotensive and hypertensive subjects following ingestion of inorganic nitrate. Oral bacteria play a key role in this process and the use of strong antibacterial mouthwash rinses can disable this mechanism. Hence, mouthwash usage, a $1.4 billion market in the US, may potentially be detrimental to cardiovascular health. The purpose of this study was to examine the effects of different strengths of commercially available mouthwash products on salivary and plasma nitrate and nitrite concentrations following 8.4 mmol inorganic nitrate load (beetroot juice). Specifically, we examined the effects of Listerine antiseptic mouthwash, Cepacol antibacterial mouthwash, and Chlorhexidine mouthwash versus control (water). Twelve apparently healthy normotensive males (36 ± 11yrs) completed four testing visits in a randomized order, separated by one week. Testing consisted of blood pressure (BP), and saliva and venous blood collection at baseline and each hour for 4 h. Following baseline-testing participants consumed 140 ml of beet juice and then 15 min later gargled with 5 mL of assigned mouthwash. Testing and mouthwash rinse was repeated every hour for 4 h. Linear mixed effects models, followed by pairwise comparisons where appropriate, were used to determine the influence of treatment and time on plasma and saliva nitrate and nitrite, and BP. Plasma and salivary nitrate increased above baseline (time effect) for all conditions (p ≤ 0.01). There were time (p ≤ 0.01), treatment (p ≤ 0.01), and interaction (p ≤ 0.05) effects for plasma and salivary nitrite. There was a treatment effect on systolic BP (p ≤ 0.05). Further examination revealed a differentiation of plasma and salivary nitrite concentration between control/antiseptic and antibacterial/chlorhexidine treatments. When examined in this manner there was a reduction in both SBP (p ≤ 0.01) and mean arterial BP (p ≤ 0.05) from the antibacterial/chlorhexidine treatments. These results suggest a potentially differentiating effect of different commercially available mouthwash solutions on plasma and salivary nitrite concentrations and resting blood pressure responses. This raises potential public health related questions on the appropriate widespread usage of different mouthwash formulations.

Heart failure with reduced ejection fraction (HFrEF) is a common end point for patients with coronary artery disease and it is characterized by exercise intolerance due, in part, to a reduction in cardiac output. Nitric oxide (NO) plays a vital role in cardiac function and patients with HFrEF have been identified as having reduced vascular NO. This pilot study aimed to investigate if nitrate supplementation could improve cardiac measures during acute, submaximal exercise. Five male participants (61 &plusmn, 3 years) with HFrEF (EF 32 &plusmn, 2.2%) completed this pilot study. All participants supplemented with inorganic nitrate (beetroot juice) or a nitrate-depleted placebo for ~13 days prior to testing. Participants completed a three-stage submaximal exercise protocol on a recumbent cycle ergometer with simultaneous echocardiography for calculation of cardiac output (Q), stroke volume (SV), and total peripheral resistance (TPR). Heart rate and blood pressure were measured at rest and during each stage. Both plasma nitrate (mean = ~1028%, p = 0.004) and nitrite (mean = ~109%, p = 0.01) increased following supplementation. There were no differences between interventions at rest, but the percent change in SV and Q from rest to stage two and stage three of exercise was higher following nitrate supplementation (all p &gt, 0.05, ES &gt, 0.8). Both interventions showed decreases in TPR during exercise, but the percent reduction TPR in stages two and three was greater following nitrate supplementation (p = 0.09, ES = 0.98 and p = 0.14, ES = 0.82, respectively). There were clinically relevant increases in cardiac function during exercise following supplementation with nitrate. The findings from this pilot study warrant further investigation in larger clinical trials.

Oral consumption of inorganic nitrate, which is abundant in green leafy vegetables and roots, has been shown to increase circulating plasma nitrite concentration, which can be converted to nitric oxide in low oxygen conditions. The associated beneficial physiological effects include a reduction in blood pressure, modification of platelet aggregation, and increases in limb blood flow. There have been numerous studies of nitrate supplementation in healthy recreational and competitive athletes; however, the ergogenic benefits are currently unclear due to a variety of factors including small sample sizes, different dosing regimens, variable nitrate conversion rates, the heterogeneity of participants’ initial fitness levels, and the types of exercise tests used. In clinical populations, the study results seem more promising, particularly in patients with cardiovascular diseases who typically present with disruptions in the ability to transport oxygen from the atmosphere to working tissues and reduced exercise tolerance. Many of these disease-related, physiological maladaptations, including endothelial dysfunction, increased reactive oxygen species, reduced tissue perfusion, and muscle mitochondrial dysfunction, have been previously identified as potential targets for nitric oxide restorative effects. This review is the first of its kind to outline the current evidence for inorganic nitrate supplementation as a therapeutic intervention to restore exercise tolerance and improve quality of life in patients with cardiovascular diseases. We summarize the factors that appear to limit or maximize its effectiveness and present a case for why it may be more effective in patients with cardiovascular disease than as ergogenic aid in healthy populations.

Rationale: A primary goal of therapy for patients with peripheral artery disease (PAD) and intermittent claudication is increased ambulatory function. Supervised exercise rehabilitation was recently shown to confer superior walking benefits to pharmacological or surgical interventions. Increases in plasma inorganic nitrite, via oral nitrate, have been shown to increase exercise performance in both human and animal models, especially in hypoxic conditions. Objective: To determine whether a 36-session exercise rehabilitation program while consuming oral inorganic nitrate (4.2 mmol concentrated beetroot juice) would produce superior benefits over exercise plus placebo in pain-free walking and markers of increased skeletal muscle perfusion in patients with PAD and intermittent claudication. Methods and Results: This was a randomized, double-blind, per-protocol study design. After the 12-week protocol, claudication onset time on a maximal treadmill test increased by 59.2±57.3 s for the exercise plus placebo group (n=13) and by 180.3±46.6 s for the exercise plus beetroot juice group (n=11; P ≤0.05). This produced a between treatment medium to large standardized effect size (Cohen d) of 0.62 (95% CI, −0.23 to +1.44). The data for 6-minute walk distance showed a similar pattern with increases of 24.6±12.1 and 53.3±19.6 m ( P ≤0.05) in the exercise plus placebo and exercise plus beetroot juice groups, respectively. Measures of gastrocnemius perfusion, including ankle-brachial index, peak reactive hyperemic blood flow, and tissue deoxygenation characteristics, during exercise (assessed my near-infrared spectroscopy) all changed significantly for the exercise plus beetroot juice group with moderate-to-large effect sizes over exercise plus placebo changes. Conclusions: Although it is premature to speculate on overall clinical utility of a nitrate-based therapy for PAD, this early pilot study evidence is encouraging. Specifically, our data suggests that increasing plasma nitrite before exercise may allow PAD subjects to train with less pain, at higher workloads for longer durations at each training session, thereby maximizing the beneficial peripheral vascular and skeletal muscle adaptations. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01684930 and NCT01785524.

Background: Chronic heart failure is characterized by an inability of the heart to pump enough blood to meet the demands of the body, resulting in the hallmark symptom of exercise intolerance. Chronic underperfusion of the peripheral tissues and impaired nitric oxide bioavailability have been implicated as contributors to the decrease in exercise capacity in these patients. nitric oxide bioavailability has been identified as an important mediator of exercise tolerance in healthy individuals, but there are limited studies examining the effects in patients with chronic heart failure. Objective: The proposed trial is designed to determine the effects of chronic inorganic nitrate supplementation on exercise tolerance in both patients with heart failure preserved ejection fraction (HFpEF) and heart failure reduced ejection fraction (HFrEF) and to determine whether there are any differential responses between the 2 cohorts. A secondary objective is to provide mechanistic insights into the 2 heart failure groups’ exercise responses to the nitrate supplementation. Methods: Patients with chronic heart failure (15=HFpEF and 15=HFrEF) aged 40 to 85 years will be recruited. Following an initial screen cardiopulmonary exercise test, participants will be randomly allocated in a double-blind fashion to consume either a nitrate-rich beetroot juice (16 mmol nitrate/day) or a nitrate-depleted placebo (for 5 days). Participants will continue daily dosing until the completion of the 4 testing visits (maximal cardiopulmonary exercise test, submaximal exercise test with echocardiography, vascular function assessment, and vastus lateralis muscle biopsy). There will then be a 2-week washout period after which the participants will cross over to the other treatment and complete the same 4 testing visits. Results: This study is funded by National Heart Foundation of Australia and Victoria University. Enrolment has commenced and the data collection is expected to be completed in mid 2018. The initial results are expected to be submitted for publication by the end of 2018. Conclusions: If inorganic nitrate supplementation can improve exercise tolerance in patients with chronic heart failure, it has the potential to aid in further refining the treatment of patients in this population. Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12615000906550; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368912 (Archived by WebCite at http://www.webcitation.org/6xymLMiFK) [JMIR Res Protoc 2018;7(4):e86]

BACKGROUND Chronic heart failure is characterized by an inability of the heart to pump enough blood to meet the demands of the body, resulting in the hallmark symptom of exercise intolerance. Chronic underperfusion of the peripheral tissues and impaired nitric oxide bioavailability have been implicated as contributors to the decrease in exercise capacity in these patients. nitric oxide bioavailability has been identified as an important mediator of exercise tolerance in healthy individuals, but there are limited studies examining the effects in patients with chronic heart failure. OBJECTIVE The proposed trial is designed to determine the effects of chronic inorganic nitrate supplementation on exercise tolerance in both patients with heart failure preserved ejection fraction (HFpEF) and heart failure reduced ejection fraction (HFrEF) and to determine whether there are any differential responses between the 2 cohorts. A secondary objective is to provide mechanistic insights into the 2 heart failure groups’ exercise responses to the nitrate supplementation. METHODS Patients with chronic heart failure (15=HFpEF and 15=HFrEF) aged 40 to 85 years will be recruited. Following an initial screen cardiopulmonary exercise test, participants will be randomly allocated in a double-blind fashion to consume either a nitrate-rich beetroot juice (16 mmol nitrate/day) or a nitrate-depleted placebo (for 5 days). Participants will continue daily dosing until the completion of the 4 testing visits (maximal cardiopulmonary exercise test, submaximal exercise test with echocardiography, vascular function assessment, and vastus lateralis muscle biopsy). There will then be a 2-week washout period after which the participants will cross over to the other treatment and complete the same 4 testing visits. RESULTS This study is funded by National Heart Foundation of Australia and Victoria University. Enrolment has commenced and the data collection is expected to be completed in mid 2018. The initial results are expected to be submitted for publication by the end of 2018. CONCLUSIONS If inorganic nitrate supplementation can improve exercise tolerance in patients with chronic heart failure, it has the potential to aid in further refining the treatment of patients in this population. CLINICALTRIAL Australian New Zealand Clinical Trials Registry ACTRN12615000906550; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368912 (Archived by WebCite at http://www.webcitation.org/6xymLMiFK)

Background: Peripheral artery disease (PAD) is caused by atherosclerotic occlusions in the legs. It affects approximately 8-12 million people in the United States alone, one-third of whom suffer from intermittent claudication (IC), defined as ischemic leg pain that occurs with walking and improves with rest. Patients with IC suffer a markedly impaired quality of life and a high perception of disability. Improving pain-free walking time is a primary goal of rehabilitation in this population. Objective: The nitric oxide (NO)-PAD trial is designed to compare the effects that 12 weeks of supervised exercise training, in combination with a high inorganic nitrate-content (beetroot [BR] juice) beverage or placebo (PL) beverage, has on clinical outcomes of exercise and functional capacity in two groups of PAD+IC patients: exercise training plus beetroot (EX+BR) and exercise training plus placebo (EX+PL). The primary aims of this randomized controlled, double-blind pilot study are to determine group differences following 12 weeks of EX+BR versus EX+PL in the changes for (1) exercise capacity: pain-free walking time (claudication onset time, COT), peak walk time (PWT), and maximal exercise capacity (peak oxygen uptake, VO2peak) during a maximal-graded cardiopulmonary exercise test (max CPX) and (2) functional capacity: 6-minute walk (6MW) distance. The secondary aims will provide mechanistic insights into the exercise outcome measures and will include (1) gastrocnemius muscle oxygenation during exercise via near-infrared spectroscopy (NIRS); (2) gastrocnemius muscle angiogenesis: capillaries per unit area and per muscle fiber, and relative fraction of type I, IIa, IIb, and IId/x fibers; and (3) vascular health/function via brachial artery flow-mediated dilation, lower-limb blood flow via plethysmography, and pulse wave velocity and reflection. Methods: A total of 30 subjects between 40 and 80 years of age with PAD who are limited by IC will undergo exercise training 3 days per week for 12 weeks (ie, 36 sessions). They will be randomized to either the EX+BR or EX+PL group where participants will consume a beverage high in inorganic nitrate (4.2 mmol) or a low-nitrate placebo, respectively, 3 hours prior to each training session. Results: Data collection from this study has been completed and is in the process of analysis and write-up. While the study is too underpowered—EX+BR, n=11; EX+PL, n=13—to determine between-group differences in the primary outcomes of COT, PWT, and 6MW, preliminary observations are promising with Cohen d effect sizes of medium to large. Conclusions: Exercise training is currently the most effective therapy to increase functional capacity in PAD+IC. If the addition of inorganic nitrate to an exercise regimen elicits greater benefits, it may redefine the current standard of care for PAD+IC. Trial Registration: ClinicalTrials.gov NCT01684930; https://clinicaltrials.gov/ct2/show/NCT01684930 (Archived by WebCite at http://www.webcitation.org/6raXFyEcP) [JMIR Res Protoc 2017;6(10):e139]

Purpose The purpose of this study was to evaluate the validity and reliability of air displacement plethysmography (ADP) compared to a dual energy x‐ray absorptiometry (DXA) criterion for body composition measurement in overweight and obese women (BMI ≥ 25·0 kg m2). Subjects/Methods Twenty‐four overweight and obese women (Mean ± SD; Age: 36·6 ± 12·0 years; Height: 166·4 ± 5·8 cm; Weight: 86·5 ± 14·2 kg; Body Fat: 38·5 ± 3·7%; BMI: 31·3 ± 5·5 kg m2) were tested after an 8‐h fast. Fat mass (FM), fat‐free mass (FFM) and percent body fat (%BF) were measured by ADP and compared to values determined by the DXA criterion. FFM from DXA was calculated as lean mass plus bone mineral content. A paired samples t‐test was used to test for significant differences in the body composition variables between methods. A one‐way ANOVA along with intraclass correlation coefficient (ICC), SEM,%SEM and MD was used to represent reliability. Results Validity data comparing ADP and DXA demonstrated no significant difference in FM (ADP‐DXA FM = 0·99 kg; P = 0·113), FFM (0·98 kg; P = 0·115) and %BF (1·56%; P = 0·540). Reliability data for ADP between the first and second trials showed no significant difference in FM (P = 0·168; ICC = 0·994; SEM = 0·668), FFM (P = 0·058; ICC = 0·973; SEM = 0·892) or %BF (P = 0·121; ICC = 0·971; SEM = 0·813). Conclusions For overweight and obese women, ADP was found to be a valid measure of FM, FFM and %BF when compared with DXA. The reliability of ADP was supported for all body composition variables.

Identifying portable methods to measure body composition may be more advantageous than using body mass index (BMI) to categorize associated health consequences. Purpose: To compare the validity and reliability of a portable A-mode ultrasound (US) to a criterion three compartment model (3C) for the measurement of body composition. Methods: Forty-seven overweight and obese subjects participated in this study. Body composition was measured once via air displacement plethysmography for body density (Bd) and bioelectrical impedance spectroscopy for total body water (TBW) for the 3C calculations. Ultrasound measurements (BodyMetrix, Intelametrix) were made using an A mode, 2.5- MHz transmitter. All measurements were made on the right side of the body at 7 skinfold sites. The US software calculated percent body fat (%BF), fat mass (FM) and fat free mass (FFM) from the 7-site Jackson and Pollock equation. Results: %BF and FM, respectively, measured by the US (29.1±6.5%; 27.4±8.1 kg) was significantly lower compared to the 3C model (33.7±7.6%; 31.8±9.8 kg; p4%BF error). While the US was not valid in this population, it was reliable producing results with minimal error, suggesting this technique may be effective for tracking changes in a weight loss or clinical setting.

Beta-alanine (BA) supplementation has been shown to delay neuromuscular fatigue as a result of increased muscle carnosine concentrations. Carnosine has also been found in brain and cardiac tissue. The physical working capacity test at heart rate threshold (PWC(HRT)) is a global estimate of the onset of fatigue during exercise, influenced by central and peripheral factors. The purpose of this study was to determine the effects of 28 days of BA supplementation on the PWC(HRT). Thirty subjects (mean ± SD; age: 21·0 ± 2·1 years; body mass: 72·7 ± 14·5 kg; height: 170·1 ± 7·9 cm) were randomly assigned to BA (n = 15) or placebo (PL, n = 15) groups. Testing included eight to nine total visits: an enrolment day, physical screening, peak oxygen consumption (V(·)O(2peak)) and two PWC(HRT) assessments over 4 days. Significant differences existed between BA and PL for PWC(HRT) (P = 0·001; mean∆: BA∆ = +24·2 watts, PL∆ = +11·2 watts), but not for V(·)O(2peak) (P = 0·222), time to exhaustion (TTE; P = 0·562) or ventilatory threshold (VT; P = 0·134). Results suggest that BA may increase heart rate training threshold. These results, in combination with one previous study reporting a potential effect of BA on HR, suggest that future studies should evaluate both central and peripheral aspects of fatigue with BA intake.