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Determine serum lipid and general health/fitness alterations following a 5-month wildfire suppression season.We recruited 100 wildland firefighters (WLFFs) to a 5-month pre- to post-season observational study. Nude body mass, blood pressure (BP), grip strength, and steptest heart rate (HR) were recorded. Blood samples were collected for lipid panel analysis (total cholesterol, high density lipoproteins (HDL)-cholesterol, low density lipoproteins-cholesterol, very low density lipoproteinscholesterol, triglycerides, triglyceride:HDL-cholesterol ratio). Two-tailed dependent t tests determined statistical significance (P 0.05).There were pre- to post-season changes in nude body mass (+2 ± 4%, P = 0.001), systolic BP (-2 ± 10%, P = 0.01), step-test HR (-5 ± 10%, P 0.001), and all serum lipids (total cholesterol: +5 ± 14%, P = 0.02, HDL-cholesterol: = 1 ± 17%, P = 0.04, low density lipoproteins-cholesterol: +8 ± 22%, P = 0.02, very low density lipoproteins-cholesterol: +31 ± 49%, P 0.001, triglycerides: +30 ± 49%, P 0.001, triglyceride:HDL-cholesterol ratio: +37 ± 58%, P 0.001). Pre- to post-season diastolic BP (P = 0.12) and grip strength (P = 0.60) remained stable.WLFFs demonstrate maladaptive serum lipids and body mass alterations despite subtle aerobic fitness improvements.

Purpose Exercise-based cardiac rehabilitation (CR) is essential for treating cardiovascular disease, and modifying risk factor modification, including hypertension. Because the causes of hypertension and benefits of CR are faceted, we examined the influence of phase II CR on resting blood pressure (BP). Methods Outcomes straddle the release of the updated BP guidelines, and study emphases included CR session number, sex, race/ethnicity, insurance provider, and referring diagnosis. Results Patient files of 31 885 individuals uploaded to the Montana Outcomes Project registry indicated that lowered systolic and diastolic BP were further improved after the release of the revised BP guidelines. The CR session number was proportional to improvements in diastolic BP. Blood pressure improved independent of sex, although female patients exhibited lower diastolic BP before and after CR. Race/ethnicity analyses indicated that Asian and White patients experienced drops in systolic and diastolic BP, while diastolic BP was improved in Hispanic patients. Neither American Indian nor Black patients exhibited statistically altered BP. Medicare, Veterans Administration, and privately insured patients had lowered systolic and diastolic BP, while Medicaid patients had lower diastolic BP, and the uninsured had lower systolic BP. Blood pressure outcomes were generally improved independent of the primary referring diagnosis, while those with peripheral artery disease showed no improvements. Conclusions Findings demonstrate that phase II CR is highly effective in the control of BP, although improvements are not equally distributed to all individuals according to differences in sex, race/ethnicity, and access to insurance-funded health care.

Progressive muscle injury and weakness are hallmarks of Duchenne muscular dystrophy. We showed previously that quercetin (Q) partially protected dystrophic limb muscles from disease-related injury. As quercetin activates PGC-1α through Sirtuin-1, an NAD+-dependent deacetylase, the depleted NAD+ in dystrophic skeletal muscle may limit quercetin efficacy; hence, supplementation with the NAD+ donor, nicotinamide riboside (NR), may facilitate quercetin efficacy. Lisinopril (Lis) protects skeletal muscle and improves cardiac function in dystrophin-deficient mice; therefore, it was included in this study to evaluate the effects of lisinopril used with quercetin and NR. Our purpose was to determine the extent to which Q, NR, and Lis decreased dystrophic injury. We hypothesized that Q, NR, or Lis alone would improve muscle function and decrease histological injury and when used in combination would have additive effects. Muscle function of 11-mo-old DBA (healthy), D2-mdx (dystrophin-deficient), and D2-mdx mice was assessed after treatment with Q, NR, and/or Lis for 7 mo. To mimic typical pharmacology of patients with Duchenne muscular dystrophy, a group was treated with prednisolone (Pred) in combination with Q, NR, and Lis. At 11 mo of age, dystrophin deficiency decreased specific tension and tetanic force in the soleus and extensor digitorum longus muscles and was not corrected by any treatment. Dystrophic muscle was more sensitive to contraction-induced injury, which was partially offset in the QNRLisPred group, whereas fatigue was similar between all groups. Treatments did not decrease histological damage. These data suggest that treatment with Q, NR, Lis, and Pred failed to adequately maintain dystrophic limb muscle function or decrease histological damage. NEW & NOTEWORTHY Despite a compelling rationale and previous evidence to the contrary in short-term investigations, quercetin, nicotinamide riboside, or Lisinopril, alone or in combination, failed to restore muscle function or decrease histological injury in dystrophic limb muscle from D2-mdx mice after long-term administration. Importantly, we also found that in the D2-mdx model, an emerging and relatively understudied model of Duchenne muscular dystrophy dystrophin deficiency caused profound muscle dysfunction and histopathology in skeletal muscle.

Exercise-based cardiac rehabilitation is integral to secondary prevention in patients with coronary artery disease. Recently, the effectiveness and "superiority" of high-intensity interval training (HIIT) is a purported time-saving alternative to "traditional" moderate-intensity continuous training (MICT) in cardiac rehabilitation. The rationale for HIIT adoption is, however, not fully substantiated in the scientific literature. Established guidelines for exercise testing and training, when carefully adhered to, reduce the likelihood of triggering a cardiac event or inducing musculoskeletal injury. Clinicians should likewise consider patient risk stratification and introduce HIIT as an alternative to MICT only after patients exhibit stable and asymptomatic responses to vigorous exercise training. Although HIIT adherence appears comparable with MICT during outpatient rehabilitation, compliance drops dramatically for unsupervised exercise. Despite the enthusiasm surrounding HIIT, its main advantage over MICT appears to be short-term exercise performance outcomes and indices of vascular function. Regarding benefits to cardiovascular disease risk factor modification, management of vital signs, and measures of cardiac performance, current evidence indicates that HIIT does not outperform MICT. Long-term outcomes to HIIT are currently uncertain and logistical constraints to HIIT incorporation need additional clarification. Based on these limited findings, derived from facilities and clinicians at the forefront of cardiac rehabilitation, the routine adoption of HIIT should be viewed cautiously. In conclusion, the current review highlights numerous specific research directives that are needed before the safety and effectiveness of HIIT can be confirmed and widely adopted in patients with known or suspected coronary artery disease, especially in unsupervised, nonmedical settings.

Duchenne muscular dystrophy (DMD) is a fatal, progressive muscle disease caused by the absence of functional dystrophin protein. Previous studies in mdx mice, a common DMD model, identified impaired autophagy with lysosomal insufficiency and impaired autophagosomal degradation as consequences of dystrophin deficiency. Thus, we hypothesized that lysosomal abundance would be decreased and degradation of autophagosomes would be impaired in muscles of D2-mdx mice. To test this hypothesis, diaphragm and gastrocnemius muscles from 11 month-old D2-mdx and DBA/2J (healthy) mice were collected. Whole muscle protein from diaphragm and gastrocnemius muscles, and protein from a cytosolic fraction (CF) and a lysosome-enriched fraction (LEF) from gastrocnemius muscles, were isolated and used for western blotting. Initiation of autophagy was not robustly activated in whole muscle protein from diaphragm and gastrocnemius, however, autophagosome formation markers were elevated in dystrophic muscles. Autophagosome degradation was impaired in D2-mdx diaphragms but appeared to be maintained in gastrocnemius muscles. To better understand this muscle-specific distinction, we investigated autophagic signaling in CFs and LEFs from gastrocnemius muscles. Within the LEF we discovered that the degradation of autophagosomes was similar between groups. Further, our data suggest an expanded, though impaired, lysosomal pool in dystrophic muscle. Notably, these data indicate a degree of muscle specificity as well as model specificity with regard to autophagic dysfunction in dystrophic muscles. Stimulation of autophagy in dystrophic muscles may hold promise for DMD patients as a potential therapeutic, however, it will be critical to choose the appropriate model and muscles that most closely recapitulate findings from human patients to further develop these therapeutics.

OBJECTIVE To document the effects of wildland firefighter (WLFF) critical training (CT) on physiologic markers of muscle damage and acute overreaching. METHODS Eighteen male and three female WLFFs were studied during an 11-day CT. Upper-body (US), lower-body (LS) muscle soreness and body weight (BW) were collected daily. Blood was collected on days 1, 4, 8, and 11 to measure creatine kinase (CK), lactate dehydrogenase (LDH), cortisol, and testosterone. Skinfolds were taken on days 1 and 11 to estimate body fat (BF) and lean body weight (LBW). RESULTS CT resulted in a significant depression in BF and elevation in LBW, while main effects of time were seen in US, LS, CK, LDH, cortisol, and testosterone/cortisol ratio (P

Hypobaria and hypoxia exert independent effects on oxidative stress during exercise, while combined effectson the post-exercise recovery period remain unclear.Accordingly, this study examined the recovery period during lab-simulated hypoxic and hypobaric conditions following exercise-induced oxidative stress. Participants (n=13) performed 60-minutes of cycling (70% watts max) in a normobaric normoxic environment followed by a four-hour recovery under three conditions; 1000m normobaric normoxia (NN, 675mmHg), 4400m normobaric hypoxia (NH, 675mmHg), or 4400m hypobaric hypoxia (HH, 440mmHg). Blood samples collected at Pre, Post, 2-Hours (2-HR), and 4-Hours (4-HR) post-exercise were analyzed fora potential increase in biochemical modifications of proteins(protein carbonyls, PC; 3-nitrotyrosines, 3NT) lipids (lipid hydroperoxides, LOOH; 8-isoprostanes, 8-ISO), and antioxidant capacity (FRAP, TEAC). Gene transcripts (EPAS, HMOX1, SOD2, NFE2L2) were quantified by qRT-PCR from muscle biopsies taken Pre and Post exercise. Hypoxia and hypobaria had no effect throughout recovery. Post-exercise TEAC (p=0.041), FRAP (p=0.013), and 8-ISO (p=0.044) increased, while PC (p=0.002) and 3-NT (p=0.032) were decreased. LOOH was lower in Post (p=0.018) NH trial samples. Exercise-dependent increases occurred in NFE2L2 (p=0.003), HMXO1 (p0.001), SOD2 (p=0.046), and EPAS (p=0.038). Exercise recovery under conditions of NH and HH did not impact blood oxidative stress or redox-sensitive gene transcripts.

Introduction: Female college students (veteran and non-veteran) are exposed to cumulative stressors and trauma that may lead to an imbalanced autonomic nervous system. Yoga has emerged as an efficacious intervention for psychological and physical trauma; however, the therapeutic dose of intervening yoga is unknown. Additionally, the frequency, duration, and type of yoga needed to achieve a therapeutic dose appear to be population specific when applied to trauma victims. The purpose of the study was to examine whether a short-term trauma-informed yoga intervention altered metrics of autonomic tone as assessed by heart rate variability (HRV) in female veteran and non-veteran college students. Methods: Nine female college students (age: 33 years ± 11, veteran, n = 4, non-veteran, n = 5) engaged in trauma-informed yoga once per week for one-hour over a four-week intervention. Repeated measures ANOVA were performed on the HRV variables lnRMSSD, lnHF, lnLF, and LF:HF. Results: Findings indicated no effect of the intervention on HRV as measured by lnRMSSD (p = .116), lnHF (p = .073), lnLF (p = .316), and LF:HF (p = .131). Further, no acute alterations in HRV were observed following a single session of trauma-informed yoga (p > .05). Conclusion: The findings of the study revealed no significant effect of trauma-informed yoga on HRV following a single session or after a four-week yoga intervention.

Cardiovascular disease (CVD) is potentiated by risk factors including physical inactivity and remains a leading cause of morbidity and mortality. Although regular physical activity does not reverse atherosclerotic coronary disease, precursory exercise improves clinical outcomes in those experiencing life-threatening CVD events. Exercise preconditioning describes the cardioprotective phenotype whereby even a few exercise bouts confer short-term multifaceted protection against acute myocardial infarction. First described decades ago in animal investigations, cardioprotective mechanisms responsible for exercise preconditioning have been identified through reductionist preclinical studies, including the upregulation of endogenous antioxidant enzymes, improved calcium handling, and enhanced bioenergetic regulation during a supply-demand mismatch. Until recently, translation of this research was only inferred from clinically-directed animal models of exercise involving ischemia-reperfusion injury, and reinforced by the gene products of exercise preconditioning that are common to mammalian species. However, recent clinical investigations confirm that exercise preconditions the human heart. This discovery means that simply the initiation of a remedial exercise regimen in those with abnormal CVD risk factor profiles will provide immediate cardioprotective benefits and improved clinical outcomes following acute cardiac events. In conclusion, the prophylactic biochemical adaptations to aerobic exercise are complemented by the long-term adaptive benefits of vascular and architectural remodeling in those who adopt a physically active lifestyle.

Those who work and recreate outdoors experience woodsmoke exposure during fire season. Exercise during woodsmoke exposure harms the cardiovascular system, but the acute physiologic and biochemical responses are understudied. The purpose of this pilot laboratory-based study was to examine the effect of exercise during woodsmoke exposure on acute indicators of cardiovascular function, including heart rate variability (HRV), pulse wave velocity (PWV), blood pressure (BP), augmentation index (AIx), and blood oxidative stress.Ten participants performed 2 moderate-intensity exercise (70% V˙OA 45-min woodsmoke exposure combined with moderate-intensity exercise did not result in a statistically significant difference in HRV, PWV, BP, AIx, or oxidative stress (P0.05).Despite the known deleterious effects of smoke inhalation, moderate-intensity aerobic exercise while exposed to woodsmoke particulate matter (250 μg·m

Objectives The current laboratory study quantified blood oxidative stress to woodsmoke exposure. Methods Participants inhaled woodsmoke during three randomized crossover exercise trials (Clean Air [0 μg/m], Low Exposure [250 μg/m], and High Exposure [500 μg/m], Woodsmoke [particulate matter less than 2.5 μm, PM2.5]). Trolox equivalent antioxidant capacity (TEAC), uric acid (UA), 8-isoprostanes (8-ISO), lipid hydroperoxides (LOOH), protein carbonyls (PC), nitrotyrosine (3-NT), 8-isoprostane, and myeloperoxidase (MPO) were quantified in Pre, immediately Post, and 1- (1Hr) hour post blood samples. Results UA decreased following Low Exposure, while plasma TEAC levels increased Post and 1Hr. LOOH levels decreased 1Hr Post (High Exposure), while 8-Iso increased following both smoke trials. PC and MPO were unchanged following all trials, while 3-NT increased over Clean Air. Conclusion Blood oxidative stress occurred largely independent of PM2.5 concentrations. Future studies should employ longer duration smoke and exercise combined with physiologic parameters.

Background Pain and discomfort reported during sitting is a significant problem for aviators during prolonged missions. Previous work has determined that areas of local pressure exist during prolonged sitting in UH-60 seat systems; however, no work has examined the effects of this local pressure on measures of neurological and circulatory function. Methods A total of 30 healthy subjects completed the study in which focal pressure was applied in three conditions (no pressure, pressure to the ischial tuberosity, and pressure to the posterior thigh). We applied pressure using a purpose-built pressure application system allowing subjects to sit in a position mimicking the sitting position in a UH-60 Black Hawk helicopter and measurements were taken before, during, and after pressure application. We measured neurological function with the soleus Hoffmann reflex and sural nerve conduction velocity, and circulatory function with dynamic infrared thermography. Results We found a decrease in soleus Hoffmann reflex by 0.87 V and 0.52 V during pressure application at the posterior thigh and ischial tuberosity, respectively. No changes in nerve conduction velocity were found among the conditions during or after pressure application. Limb temperature increased 0.42-0.44°C during pressure application, but began to return to baseline once pressure was removed. Discussion This study examined the development of neurological and circulatory alterations due to local pressure application in an aviation specific functional position. These results may be used in the development of future interventions to mitigate the negative effects of localized pressure in military aviators.Games KE, Lakin JM, Quindry JC, Weimar WH, Sefton JM. Local pressure application effects on neurological and circulatory function. Aerosp Med Hum Perform. 2018; 89(8):693-699.

Background The impact of blood flow regulation and oxidative stress during exercise in cystic fibrosis (CF) has yet to be investigated. Methods A maximal graded exercise test was conducted to determine exercise capacity (VO 2 peak) and peak workload in 14 pediatric patients with mild CF (age 14±3y, FEV 1 93±16 % predicted) and 14 demographically-matched controls. On a separate visit, participants performed submaximal cycling up to 60% of peak workload where brachial artery blood velocity was determined using Doppler ultrasound. Retrograde and antegrade components were further analyzed as indices of blood flow regulation. Results The cumulative AUC for retrograde velocity was lower in patients versus controls (1770±554 vs. 3440±522cm, P =0.038). In addition, an exaggerated oxidative stress response during exercise occurred in patients only ( P =0.004). Conclusion These data suggest that patients with mild CF exhibit impaired blood flow regulation and an exaggerated oxidative stress response to submaximal exercise.

In the search for innovative solutions to treat ischemic heart disease, recent basic science and clinical approaches have focused on remote ischemic preconditioning (RIPC). Remote ischemic preconditioning involves short intervals of limb blood flow occlusion by the application of a blood pressure cuff inflated to a suprasystolic pressure. The promise of RIPC in the development of new cardioprotective therapies is founded on the premise that it is cost-effective, technically simple, and overcomes many logistical and biochemical hurdles associated with other ischemic preconditioning approaches. However, RIPC as a research subarea is still in its infancy and clinical applications for individuals at high risk of cardiovascular disease remain elusive. The thesis of the current review is that observational and mechanistic similarities between exercise-induced preconditioning and RIPC may reveal novel therapeutic links to cardioprotection. While reductionist understanding of the exercised heart is still in the formative stages, available mechanistic knowledge of exercise-induced cardioprotection is juxtaposed to RIPC and potential implications discussed. In total, additional research is needed in order to fully appreciate the mechanistic and translative connections between exercise and RIPC. Nonetheless, existing rationale are strong and suggest that RIPC approaches may be helpful in the development and application to pharmacologic interventions in those with ischemic heart disease.

New Findings What is the central question of this study? The central question of this study is to understand whether dietary quercetin enrichment attenuates physiologic, histological, and biochemical indices of cardiac pathology. What is the main finding and its importance? Novel findings from this investigation, in comparison to prior published studies, suggest that mouse strain-dependent cardiac outcomes in performance and remodelling exist. Unlike Mdx/Utrn−/+ mice, mdx mice receiving lifelong quercetin treatment did not exhibit improvements cardiac function. Similar to prior work in Mdx/Utrn−/+ mice, histological evidence of remodelling suggests that quercetin consumption may have benefited hearts of mdx mice. Positive outcomes may be related to indirect markers that suggest improved mitochondrial wellbeing and to selected indices of inflammation that were lower in hearts from quercetin-fed mice. Duchenne muscular dystrophy causes a decline in cardiac health, resulting in premature mortality. As a potential countermeasure, quercetin is a polyphenol possessing inherent anti-inflammatory and antioxidant effects that activate proliferator-activated γ coactivator 1α (PGC-1α), increasing the abundance of mitochondrial biogenesis proteins. We investigated the extent to which lifelong 0.2% dietary quercetin enrichment attenuates dystrophic cardiopathology in mdx mice. Dystrophic animals were fed a quercetin-enriched or control diet for 12 months, while control C57 mice were fed a control diet. Cardiac function was assessed via 7 T magnetic resonance imaging at 2, 10 and 14 months. At 14 months, hearts were harvested for histology and Western blotting. The results indicated an mdx strain-dependent decline in cardiac performance at 14 months and that dietary quercetin enrichment did not attenuate functional losses. In contrast, histological analyses provided evidence that quercetin feeding was associated with decreased fibronectin and indirect damage indices (Haematoxylin and Eosin) compared with untreated mdx mice. Dietary quercetin enrichment increased cardiac protein abundance of PGC-1α, cytochrome c, electron transport chain complexes I–V, citrate synthase, superoxide dismutase 2 and glutathione peroxidase (GPX) versus untreated mdx mice. The protein abundance of the inflammatory markers nuclear factor-κB, phosphorylated nuclear factor kappa beta (P-NFκB) and phosphorylated nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (P-IKBα) was decreased by quercetin compared with untreated mdx mice, while preserving nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha( IKBα) compared with mdx mice. Furthermore, quercetin decreased transforming growth factor-β1, cyclooxygenase-2 (COX2) and macrophage-restricted F4/80 protein (F4/80) versus untreated mdx mice. The data suggest that long-term quercetin enrichment does not impact physiological parameters of cardiac function but improves indices of mitochondrial biogenesis and antioxidant enzymes, facilitates dystrophin-associated glycoprotein complex (DGC) assembly and decreases inflammation in dystrophic hearts.

Inactivity leads to morbidity and mortality, while novel and engaging approaches to fitness improve health outcomes. The current study examined an 8-week commercial group exercise regimen for high intensity interval training (HIIT) in order to examine comprehensive metrics of health and fitness. Aerobic fitness, body composition, resting metabolic rate, blood cholesterol and glucose, in addition to resting blood pressure were quantified in a laboratory setting independent of the training facilities. Exercise training utilized multimodal HIIT-based exercises and work intensity was gauged by real-time heart rate feedback. All participants completed the required two sessions per week. Pre-Post analyses indicate aerobic fitness (Pre VO2max = 36.8 ml•kg-1•min-1; Post VO2max = 40.8 ml•kg-1•min-1), % fat (Pre = 28.1%; Post = 27.0%), resting metabolic rate (Pre = 1557 kcals; Post = 1664 kcals), resting blood pressure (Pre = 128.8/78.1 mmHg; Post = 116.7/75.4 mmHg), and circulating triacylglycerol (Pre = 100.0 mg/dl; Post = 78.7 mg/dl) were significantly altered. This study quantified improvements in aerobic fitness, body composition, resting metabolic rate, resting blood pressure, and triacylglycerol after an 8-week HIIT regimen. The implications of heart rate (HR) monitoring within franchised group exercise with wearable technology serves as an unexplored scientific approach to understand novel exercise prescriptions on health-fitness outcomes. Future research should investigate sociological aspects of program adherence, while biological applications should examine the adaptive stimuli of HIIT training on health and fitness improvements. This work was supported by the Ultimate Fitness Group, LLC dba Orange Theory Fitness.

Background Duchenne muscular dystrophy is a muscle wasting disease caused by dystrophin gene mutations resulting in dysfunctional dystrophin protein. Autophagy, a proteolytic process, is impaired in dystrophic skeletal muscle though little is known about the effect of dystrophin deficiency on autophagy in cardiac muscle. We hypothesized that with disease progression autophagy would become increasingly dysfunctional based upon indirect autophagic markers. Methods Markers of autophagy were measured by western blot in 7-week-old and 17-month-old control (C57) and dystrophic (mdx) hearts. Results Counter to our hypothesis, markers of autophagy were similar between groups. Given these surprising results, two independent experiments were conducted using 14-month-old mdx mice or 10-month-old mdx/Utrn± mice, a more severe model of Duchenne muscular dystrophy. Data from these animals suggest increased autophagosome degradation. Conclusion Together these data suggest that autophagy is not impaired in the dystrophic myocardium as it is in dystrophic skeletal muscle and that disease progression and related injury is independent of autophagic dysfunction.

NEW FINDINGS What is the central question of this study? We previously demonstrated that quercetin transiently preserved respiratory function in dystrophin-deficient mice. To gain lasting therapeutic benefits, we tested quercetin in combination with nicotinamide riboside, lisinopril and prednisolone in the D2-mdx model. What is the main finding and its importance? We demonstrated that these quercetin-based cocktails did not preserve respiratory or diaphragmatic function or reduce histological damage after 7 months of treatment starting at 4 months of age. ABSTRACT Duchenne muscular dystrophy is characterized by the absence of dystrophin protein and causes muscle weakness and muscle injury, culminating in respiratory failure and cardiomyopathy. Quercetin transiently improved respiratory function but failed to maintain long-term therapeutic benefits in mdx mice. In this study, we combined quercetin with nicotinamide riboside (NR), lisinopril and prednisolone to assess the efficacy of quercetin-based cocktails. We hypothesized that quercetin, NR and lisinopril independently would improve respiratory function and decrease diaphragmatic injury and when combined would have additive effects. To address this hypothesis, in vivo respiratory function, in vitro diaphragmatic function and histological injury were assessed in DBA (healthy), D2-mdx (dystrophic) and D2-mdx mice treated with combinations of quercetin, NR and lisinopril from 4 to 11 months of age. Respiratory function, assessed using whole-body plethysmography, was largely similar between healthy and dystrophin-deficient mice. Diaphragm specific tension was decreased by ∼50% in dystrophic mice compared with healthy mice (P

Duchenne Muscular Dystrophy (DMD) is associated with progressive cardiac pathology; however, the SIRT1/PGC1-α activator quercetin may cardioprotect dystrophic hearts. We tested the extent to which long-term 0.2% dietary quercetin enrichment attenuates dystrophic cardiopathology in Mdx/Utrn+/− mice. At 2 mo, Mdx/Utrn+/− mice were fed quercetin-enriched (Mdx/Utrn+/−-Q) or control diet (Mdx/Utrn+/−) for 8 mo. Control C57BL/10 (C57) animals were fed a control diet for 10 mo. Cardiac function was quantified by MRI at 2 and 10 mo. Spontaneous physical activity was quantified during the last week of treatment. At 10 mo hearts were excised for histological and biochemical analysis. Quercetin feeding improved various physiological indexes of cardiac function in diseased animals. Mdx/Utrn+/−-Q also engaged in more high-intensity physical activity than controls. Histological analyses of heart tissues revealed higher expression and colocalization of utrophin and α-sarcoglycan. Lower abundance of fibronectin, cardiac damage (Hematoxylin Eosin-Y), and MMP9 were observed in quercetin-fed vs. control Mdx/Utrn+/− mice. Quercetin evoked higher protein abundance of PGC-1α, cytochrome c, ETC complexes I–V, citrate synthase, SOD2, and GPX compared with control-fed Mdx/Utrn+/−. Quercetin decreased abundance of inflammatory markers including NFκB, TGF-β1, and F4/80 compared with Mdx/Utrn+/−; however, P-NFκB, P-IKBα, IKBα, CD64, and COX2 were similar between groups. Dietary quercetin enrichment improves cardiac function in aged Mdx/Utrn+/− mice and increases mitochondrial protein content and dystrophin glycoprotein complex formation. Histological analyses indicate a marked attenuation in pathological cardiac remodeling and indicate that long-term quercetin consumption benefits the dystrophic heart. NEW & NOTEWORTHY The current investigation provides first-time evidence that quercetin provides physiological cardioprotection against dystrophic pathology and is associated with improved spontaneous physical activity. Secondary findings suggest that quercetin-dependent outcomes are in part due to PGC-1α pathway activation.

INTRODUCTION Despite significant investment into the development and improvement of military helicopter seat systems, military aviators continue to report seat system related pain and discomfort during prolonged missions. METHODS Using a factorial repeated measures design, 15 healthy subjects completed the study, in which focal pressure was applied to two locations on the sitting surfaces of the body (ischial tuberosity and middle of the posterior thigh). Pressure was applied using a purpose-built pressure application system allowing subjects to sit in a position mimicking the sitting position in the UH-60 Black Hawk helicopter. The researchers measured pain using the Category Partitioning Scale and McGill Pain Questionnaire and vascular function using dynamic infrared thermography in the lower leg and pulse oximetry at the great toe. Data were collected before and during a 10-min application of focal pressure applied to either the ischial tuberosity or middle of the posterior thigh and at two different pressure magnitudes (36 or 44 kPa). RESULTS We found that during a 10-min pressure application, superficial skin temperature increased by 0.61°C, suggesting a decreased venous return during pressure application. We found that lower extremity blood oxygenation remained unchanged during pressure application. Subjects' reported pain increased during pressure application and was greater with 44 kPa of application compared to 36 kPa. DISCUSSION These results support the hypothesis that locally high pressure creates symptoms of discomfort and paresthesia. Research examining the effects of local pressure application on physiological and neurological function is needed. Games KE, Lakin JM, Quindry JC, Weimar WH, Sefton JM. Local pressure application effects on discomfort, temperature, and limb oxygenation. Aerosp Med Hum Perform. 2016; 87(8):697-703.

Key point PGC-1α pathway activation has been shown to decrease disease severity and can be driven by quercetin. Oral quercetin supplementation protected respiratory function for 4-6 months during a 12 month dosing regimen. This transient protection was probably due to a failure to sustain elevated SIRT1 activity and downstream PGC-1α signalling. Quercetin supplementation may be a beneficial treatment as part of a cocktail provided continued SIRT1 activity elevation is achieved. Abstract Duchenne muscular dystrophy (DMD) impacts 1 : 3500 boys and leads to muscle dysfunction culminating in death due to respiratory or cardiac failure. There is an urgent need for effective therapies with the potential for immediate application for this patient population. Quercetin, a flavonoid with an outstanding safety profile, may provide therapeutic relief to DMD patients as the wait for additional therapies continues. This study evaluated the capacity of orally administered quercetin (0.2%) in 2 month old mdx mice to improve respiratory function and end-point functional and histological outcomes in the diaphragm following 12 months of treatment. Respiratory function was protected for the first 4-6 months of treatment but appeared to become insensitive to quercetin thereafter. Consistent with this, end-point functional measures were decreased and histopathological measures were more severe in dystrophic muscle compared to C57 and similar between control-fed and quercetin-fed mdx mice. To better understand the transient nature of improved respiratory function, we measured PGC-1α pathway activity, which is suggested to be up-regulated by quercetin supplementation. This pathway was largely suppressed in dystrophic muscle compared to healthy muscle, and at the 14 month time point dietary quercetin enrichment did not increase expression of downstream effectors. These data support the efficacy of quercetin as an intervention for DMD in skeletal muscle, and also indicate the development of age-dependent quercetin insensitivity when continued supplementation fails to drive the PGC-1α pathway. Continued study is needed to determine if this is related to disease severity, age or other factors.

A controlled human exposure study was conducted to investigate the impact of inhalational exposures to wood smoke PM2.5 on measured concentrations of airway and systemic inflammatory biomarkers.Mimicking wildland firefighter activities, 10 participants were exposed to three doses of wood smoke PM2.5 (filtered-air, 250 μg/m, and 500 μg/m) while exercising on a treadmill. Exhaled breath condensate (EBC) and blood plasma samples were obtained pre-, immediately post-, and 1-hour postexposure. 8-isoprostane, pH, and myeloperoxidase were measured in EBC, while H2O2, surfactant protein D, and pentraxin-3 (PTX3) were measured in both EBC and plasma.Only pH, 8-isoprostane, and PTX3 displayed significant changes when comparing pre- and postexposures.Markers of inflammation and oxidative stress, including PTX3, pH, and 8-isoprostane in EBC and/or plasma, are sensitive to wood smoke inhalation, with further investigations warranted.

Exercise and oxidative stress research continues to grow as a physiological subdiscipline. The influence of high altitude on exercise and oxidative stress is among the recent topics of intense study in this area. Early findings indicate that exercise at high altitude has an independent influence on free radical generation and the resultant oxidative stress. This review provides a detailed summary of oxidative stress biochemistry as gleaned mainly from studies of humans exercising at high altitude. Understanding of the human response to exercise at altitude is largely derived from field-based research at altitudes above 3000 m in addition to laboratory studies which employ normobaric hypoxia. The implications of oxidative stress incurred during high altitude exercise appear to be a transient increase in oxidative damage followed by redox-sensitive adaptations in multiple tissues. These outcomes are consistent for lowland natives, high altitude acclimated sojourners and highland natives, although the latter group exhibits a more robust adaptive response. To date there is no evidence that altitude-induced oxidative stress is deleterious to normal training or recovery scenarios. Limited evidence suggests that deleterious outcomes related to oxidative stress are limited to instances where individuals are exposed to extreme elevations for extended durations. However, confirmation of this tentative conclusion requires further investigation. More applicably, altitude-induced hypoxia may have an independent influence on redox-sensitive adaptive responses to exercise and exercise recovery. If correct, these findings may hold important implications for athletes, mountaineers, and soldiers working at high altitude. These points are raised within the confines of published research on the topic of oxidative stress during exercise at altitude.

Whole body plethysmography (WBP) is used to quantify pulmonary function in conscious, unrestrained mice. We determined currently whether time of day and environmental lighting influence day-to-day reproducibility of pulmonary function, and quantifed the necessary habituation time in the WBP chamber. Two-month-old male C57BL6 and mdx mice (n = 8/group, reverse light cycle), were examined on consecutive days using a calibrated WBP chamber and manufacturer software was used to calculate respiratory measures. Respiratory data stabilized between 5-10 min for all variables. Mice exhibited time of day respiratory differences, performing more forceful and less frequent breaths midday (11:45 a.m. and 3:00 p.m.) compared to 7:30 a.m. WBP performed in darkened conditions elicited more forceful breathing than lit conditions. Day-to-day reproducibility during controlled conditions ranged from r(2) = 0.58 to 0.62 for the functional measures. Findings indicate reproducible respiratory data are obtainable following a 15-min chamber habituation and standardization of time of day and room lighting.

Doxorubicin (DOX) is a highly effective anti-neoplastic agent; however, its cumulative dosing schedules are clinically limited by the development of cardiotoxicity. Previous studies have attributed the cause of DOX-mediated cardiotoxicity to mitochondrial iron accumulation and the ensuing reactive oxygen species (ROS) formation. The present study investigates the role of frataxin (FXN), a mitochondrial iron-sulfur biogenesis protein, and its role in development of DOX-mediated mitochondrial dysfunction. Athymic mice treated with DOX (5 mg/kg, 1 dose/wk with treatments, followed by 2-wk recovery) displayed left ventricular hypertrophy, as observed by impaired cardiac hemodynamic performance parameters. Furthermore, we also observed significant reduction in FXN expression in DOX-treated animals and H9C2 cardiomyoblast cell lines, resulting in increased mitochondrial iron accumulation and the ensuing ROS formation. This observation was paralleled in DOX-treated H9C2 cells by a significant reduction in the mitochondrial bioenergetics, as observed by the reduction of myocardial energy regulation. Surprisingly, similar results were observed in our FXN knockdown stable cell lines constructed by lentiviral technology using short hairpin RNA. To better understand the cardioprotective role of FXN against DOX, we constructed FXN overexpressing cardiomyoblasts, which displayed cardioprotection against mitochondrial iron accumulation, ROS formation, and reduction of mitochondrial bioenergetics. Lastly, our FXN overexpressing cardiomyoblasts were protected from DOX-mediated cardiac hypertrophy. Together, our findings reveal novel insights into the development of DOX-mediated cardiomyopathy.

Interleukin-6 (IL-6) is a pleiotropic cytokine that protects against cardiac ischemia-reperfusion (I/R) injury following pharmacological and ischemic preconditioning (IPC), but the affiliated role in exercise preconditioning is unknown. Our study purpose was to characterize exercise-induced IL-6 cardiac signaling ( aim 1) and evaluate myocardial preconditioning ( aim 2). In aim 1, C57 and IL-6−/− mice underwent 3 days of treadmill exercise for 60 min/day at 18 m/min. Serum, gastrocnemius, and heart were collected preexercise, immediately postxercise, and 30 and 60 min following the final exercise session and analyzed for indexes of IL-6 signaling. For aim 2, a separate cohort of exercise-preconditioned (C57 EX and IL-6−/− EX) and sedentary (C57 SED and IL-6−/− SED) mice received surgical I/R injury (30 min I, 120 min R) or a time-matched sham operation. Ischemic and perfused tissues were examined for necrosis, apoptosis, and autophagy. In aim 1, serum IL-6 and IL-6 receptor (IL-6R), gastrocnemius, and myocardial IL-6R were increased following exercise in C57 mice only. Phosphorylated (p) signal transducer and activator of transcription 3 was increased in gastrocnemius and heart in C57 and IL-6−/− mice postexercise, whereas myocardial iNOS and cyclooxygenase-2 were unchanged in the exercised myocardium. Exercise protected C57 EX mice against I/R-induced arrhythmias and necrosis, whereas arrhythmia score and infarct outcomes were higher in C57 SED, IL-6−/− SED, and IL-6−/− EX mice compared with SH. C57 EX mice expressed increased p-p44/42 MAPK (Thr202/Tyr204) and p-p38 MAPK (Thr180/Tyr182) compared with IL-6−/− EX mice, suggesting pathway involvement in exercise preconditioning. Findings indicate exercise exerts cardioprotection via IL-6 and strongly implicates protective signaling originating from the exercised skeletal muscle.

Altitude exposure and exercise elicit oxidative stress in blood; however, exercise recovery at 5000 m attenuates oxidative stress. The purpose was to determine the altitude threshold at which blood oxidative stress is blunted during exercise recovery. Twelve males 18-28 years performed four-cycle ergometry bouts (60 min, 70% VO2max, at 975 m). In a randomised counterbalanced crossover design, participants recovered 6 h at 0, 1667, 3333 and 5000 m in a normobaric hypoxia chamber (recovery altitudes were simulated by using a computerised system in an environmental chamber by lowering the partial pressure of oxygen to match that of the respective altitude). Oxygen saturation was monitored throughout exercise recovery. Blood samples obtained pre-, post-, 1 h post- and 5 h post-exercise were assayed for ferric-reducing antioxidant plasma, Trolox equivalent antioxidant capacity, uric acid, lipid hydroperoxides and protein carbonyls. Muscle biopsies obtained pre and 6 h were analysed by real-time polymerase chain reaction to quantify expression of hemeoxgenase 1, superoxide dismutase 2 and nuclear factor (euthyroid-derived 2)-like factor. Pulse oximetry data were similar during exercise, but decreased for the three highest recovery elevations (0 m = 0%, 1667 m = -3%; 3333 m = -7%; 5000 m = -17%). A time-dependent oxidative stress occurred following exercise for all variables, but the two highest recovery altitudes partially attenuated the lipid hydroperoxide response (0 m = +135%, 1667 m = +251%, 3333 m = +99%; 5000 m = +108%). Data may indicate an altitude threshold between 1667 and 3333 m, above which the oxidative stress response is blunted during exercise recovery.

New Findings What is the central question of this study? Does the δ-opioid receptor trigger exercise-induced cardioprotection against ischaemia–reperfusion injury? What is the main finding and its importance? In exercised hearts, the δ-opioid receptor appears to trigger cardioprotection against ischaemia–reperfusion-induced tissue necrosis but not apoptosis. Abstract Endogenous opioids mediate exercise-induced cardioprotection against ischaemia–reperfusion (IR) injury, although the opioid receptor subtype mediating this effect is unknown. We investigated whether the δ-opioid receptor mediates exercise-induced cardioprotection against IR injury. Endogenous opioids are produced in various tissues, including the heart and skeletal muscle; therefore, we also sought to identify the effect of exercise on circulating endogenous opioid as well as transcript, protein and receptor expression in heart and skeletal muscle. Male Sprague–Dawley rats (n = 73) were assigned randomly to treadmill exercise or sedentary treatments. Cardiac tissue and serum were harvested 0, 20 and 120 min following exercise and from sedentary animals (n = 32) to quantify effects on proenkephalin and δ-opioid receptor mRNA and protein levels, as well as serum enkephalin. Skeletal muscle (soleus) was harvested at identical time points for determination of proenkephalin protein and mRNA. A separate group of rats (n = 41) were randomly assigned to sham operation (Sham; surgical control), sedentary (Sed), exercise (Ex) or exercise + δ-opioid receptor antagonist (ExD; naltrindole, 5 mg kg−1 i.p.) and received IR by left anterior descending coronary artery ligation in vivo. After IR, tissues were harvested to quantify treatment effects on necrosis and apoptosis. Cardiac proenkephalin mRNA expression increased following exercise (0 min, P = 0.03; 120 min, P = 0.021), while soleus expression was unaffected. Exercise-induced changes in serum enkephalin were undetectable. After IR, tissue necrosis was elevated in Sed and ExD hearts (P

Introduction Advances in flight technologies and the demand for long-range flight have increased mission lengths for U.S. Army Black Hawk UH-60 crewmembers. Prolonged mission times have increased reports of pilot discomfort and symptoms of paresthesia thought to be due to UH-60 seat design and areas of locally high pressure. Discomfort created by the seat-system decreases situational awareness, putting aviators and support crew at risk of injury. Therefore, the purpose of this study was to examine the effects of prolonged restricted sitting in a UH-60 on discomfort, sensory function, and vascular measures in the lower extremities. Methods There were 15 healthy men (age = 23.4 ± 3.1 yr) meeting physical flight status requirements who sat in an unpadded, UH-60 pilot's seat for 4 h while completing a common cognitive task. During the session, subjective discomfort, sensory function, and vascular function were measured. Results Across 4 h of restricted sitting, subjective discomfort increased using the Category Partitioning Scale (30.27 point increase) and McGill Pain Questionnaire (8.53 point increase); lower extremity sensory function was diminished along the S1 dermatome; and skin temperature decreased on both the lateral (2.85°C decrease) and anterior (2.78°C decrease) aspects of the ankle. Discussion The results suggest that prolonged sitting in a UH-60 seat increases discomfort, potentially through a peripheral nervous or vascular system mechanism. Further research is needed to understand the etiology and onset of pain and paresthesia during prolonged sitting in UH-60 pilot seats. Games KE, Lakin JM, Quindry JC, Weimar WH, Sefton JM. Prolonged restricted sitting effects in UH-60 helicopters.

Exercise and pharmacologic therapies to prevent and treat cardiovascular disease have advanced largely through independent efforts. Understanding of first-line drug therapies, findings from preclinical animal studies, and the need for research initiatives related to complementary cardioprotective exercise-pharma interventions are reviewed from the premise that contemporary cardioprotective therapies must include adjunctive exercise and lifestyle interventions in addition to pharmacologic agents.

New Findings What is the central question of this study? Does dietary quercetin enrichment improve biochemical and histological outcomes in hearts from mdx mice? What is the main finding and what is its importance? Biochemical and histological findings suggest that chronic quercetin feeding of mdx mice may improve mitochondrial function and attenuate tissue pathology. Patients with Duchenne muscular dystrophy suffer from cardiac pathology, which causes up to 40% of all deaths because of fibrosis and cardiac complications. Quercetin is a flavonol with anti-inflammatory and antioxidant effects and is also an activator of peroxisome proliferator-activated receptor γ coactivator 1α capable of antioxidant upregulation, mitochondrial biogenesis and prevention of cardiac complications. We sought to determine the extent to which dietary quercetin enrichment prevents (experiment 1) and rescues cardiac pathology (experiment 2) in mdx mice. In experiment 1, 3-week-old mdx mice were fed control chow (C3w6m, n = 10) or chow containing 0.2% quercetin for 6 months (Q3w6m, n = 10). In experiment 2, 3-month-old mdx mice were fed control chow (C3m6m, n = 10) or 0.2% chow containing 0.2% quercetin for 6 months (Q3m6m, n = 10). Hearts were excised for histological and biochemical analyses. In experiment 1, Western blot targets for mitochondrial biogenesis (cytochrome c, P = 0.007) and antioxidant expression (superoxide dismutase 2, P = 0.014) increased in Q3w6m mice compared with C3w6m. Histology revealed increased utrophin (P = 0.025) and decreased matrix metalloproteinase 9 abundance (P = 0.040) in Q3w6m mice compared with C3w6m. In experiment 2, relative (P = 0.023) and absolute heart weights (P = 0.020) decreased in Q3m6m mice compared with C3m6m. Indications of damage (Haematoxylin- and Eosin-stained sections, P = 0.007) and Western blot analysis of transforming growth factor β1 (P = 0.009) were decreased in Q3m6m mice. Six months of quercetin feeding increased a mitochondrial biomarker, antioxidant protein and utrophin and decreased matrix metalloproteinase 9 in young mice. Given that these adaptations are associated with attenuated cardiac pathology and damage, the present findings may indicate that dietary quercetin enrichment attenuates dystrophic cardiac pathology, but physiological confirmation is needed.

Hypoxia due to altitude diminishes performance and alters exercise oxidative stress responses. While oxidative stress and exercise are well studied, the independent impact of hypoxia on exercise recovery remains unknown. Accordingly, we investigated hypoxic recovery effects on post-exercise oxidative stress. Physically active males (n = 12) performed normoxic cycle ergometer exercise consisting of ten high:low intensity intervals, 20 min at moderate intensity, and 6 h recovery at 975 m (normoxic) or simulated 5,000 m (hypoxic chamber) in a randomized counter-balanced cross-over design. Oxygen saturation was monitored via finger pulse oximetry. Blood plasma obtained pre- (Pre), post- (Post), 2 h post- (2Hr), 4 h post- (4Hr), and 6 h (6Hr) post-exercise was assayed for Ferric Reducing Ability of Plasma (FRAP), Trolox Equivalent Antioxidant Capacity (TEAC), Lipid Hydroperoxides (LOOH), and Protein Carbonyls (PC). Biopsies from the vastus lateralis obtained Pre and 6Hr were analyzed by real-time PCR quantify expression of Heme oxygenase 1 (HMOX1), Superoxide Dismutase 2 (SOD2), and Nuclear factor (euthyroid-derived2)-like factor (NFE2L2). PCs were not altered between trials, but a time effect (13 % Post-2Hr increase, p = 0.044) indicated exercise-induced blood oxidative stress. Plasma LOOH revealed only a time effect (p = 0.041), including a 120 % Post-4Hr increase. TEAC values were elevated in normoxic recovery versus hypoxic recovery. FRAP values were higher 6Hr (p = 0.045) in normoxic versus hypoxic recovery. Exercise elevated gene expression of NFE2L2 (20 % increase, p = 0.001) and SOD2 (42 % increase, p = 0.003), but hypoxic recovery abolished this response. Data indicate that recovery in a hypoxic environment, independent of exercise, may alter exercise adaptations to oxidative stress and metabolism.

Myocardial ischemia-reperfusion (IR) injury can cause ventricular cell death and is a major pathological event leading to morbidity and mortality in those with coronary artery disease. Interestingly, as few as five bouts of exercise on consecutive days can rapidly produce a cardiac phenotype that resists IR-induced myocardial injury. This review summarizes the development of exercise-induced cardioprotection and the mechanisms responsible for this important adaptive response.

Cardiovascular disease (CVD), including ischemia reperfusion (IR) injury, remains a major cause of morbidity and mortality in industrialized nations. Ongoing research is aimed at uncovering therapeutic interventions against IR injury. Regular exercise participation is recognized as an important lifestyle intervention in the prevention and treatment of CVD and IR injury. More recent understanding reveals that moderate intensity aerobic exercise is also an important experimental model for understanding the cellular mechanisms of cardioprotection against IR injury. An important discovery in this regard was the observation that one-to-several days of exercise will attenuate IR injury. This phenomenon has been observed in young and old hearts of both sexes. Due to the short time course of exercise induced protection, IR injury prevention must be mediated by acute biochemical alterations within the myocardium. Research over the last decade reveals that redundant mechanisms account for exercise induced cardioprotection against IR. While much is now known about exercise preconditioning against IR injury, many questions remain. Perhaps most pressing, is what mechanisms mediate cardioprotection in aged hearts and what sex-dependent differences exist. Given that that exercise preconditioning is a polygenic effect, it is likely that multiple mediators of exercise induced cardioprotection have yet to be uncovered. Also unknown, is whether post translational modifications due to exercise are responsible for IR injury prevention. This review will provide an overview the major mechanisms of IR injury and exercise preconditioning. The discussion highlights many promising avenues for further research and describes how exercise preconditioning may continue to be an important scientific paradigm in the translation of cardioprotection research to the clinic.

Patients with diabetes exhibit significantly altered renin-angiotensin system (RAS) control. Recently, it has been determined that hyperglycemic conditions induce an increase in angiotensin II (AT II) expression; specifically by cardiomyocytes. Altered RAS has been shown to be associated with an increase in oxidative stress and cardiac dysfunction leading to the development of cardiac hypertrophy. The transient outward potassium current (I(to)) in cardiac myocytes is mainly mediated by members of the Kv subfamily of voltage gated potassium channels and has been shown to be altered in cellular localization and expression during the development of cardiac hypertrophy. However it is not clear as to how AT II affects the pore forming complex at the cell membrane and thus directly affects the I(to) current. In the current study, we explored the protective effect of PPARγ ligands on cardiomyocyte I(to) by preventing NADPH Oxidase activation and the ensuing ROS formation. Furthermore, short term PPARγ activation in diabetic leptin deficient db/db mice displayed improvements in the membrane association of the molecular components of I(to) as well as prolonged QT interval. These findings demonstrate that PPARγ agonists have the potential to attenuate cardiomyocyte dysfunction associated with diabetes.