The Interaction of Duchenne Muscular Dystrophy and Insulin Resistance.

Duchenne muscular dystrophy (DMD), caused by deficiency of functional dystrophin protein, is a fatal, progressive muscle disease that frequently includes metabolic dysregulation. Herein, we explore the physiologic consequences of dystrophin deficiency within the context of obesity and insulin resistance. We hypothesized that dystrophin deficiency increases the frequency of insulin resistance, and insulin resistance potentiates muscle pathology caused by dystrophin deficiency.

Cardiovascular and Blood Oxidative Stress Responses to Exercise and Acute Woodsmoke Exposure in Recreationally Active Individuals.

INTRODUCTION: 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. METHODS: Ten participants performed 2 moderate-intensity exercise (70% V˙O2 max) trials (clean air 0 µg·m-3, woodsmoke 250 µg·m-3) in a crossover design. HRV, PWV, BP, AIx, and blood oxidative stress were measured before, after, and 90 min after exercise for each trial. Blood oxidative stress was quantified through lipid damage (LOOH, 8-ISO), protein damage (3-NT, PC), and antioxidant capacity (TEAC). RESULTS: A 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 (P>0.05). CONCLUSIONS: Despite the known deleterious effects of smoke inhalation, moderate-intensity aerobic exercise while exposed to woodsmoke particulate matter (250 µg·m-3) did not result in a statistically significant difference in HRV, PWV, or blood oxidative stress in this methodologic context. Although findings do not negate the negative impact of woodsmoke inhalation, additional research approaches are needed to better understand the acute effects of smoke exposure on the cardiovascular system.

Blood oxidative stress and post-exercise recovery are unaffected byhypobaric and hypoxic environments.

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 (p<0.001), 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.

Cardioprotective Exercise and Pharmacologic Interventions as Complementary Antidotes to Cardiovascular Disease.

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.

Lifelong quercetin enrichment and cardioprotection in Mdx/Utrn+/- mice.

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-ß1, 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.

Long-term dietary quercetin enrichment as a cardioprotective countermeasure in mdx mice.

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-ß1, 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.

Consensus Statement Immunonutrition and Exercise.

In this consensus statement on immunonutrition and exercise, a panel of knowledgeable contributors from across the globe provides a consensus of updated science, including the background, the aspects for which a consensus actually exists, the controversies and, when possible, suggested directions for future research.

Oral quercetin administration transiently protects respiratory function in dystrophin-deficient mice.

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.

Autonomic Responses to an Acute Bout of High-Intensity Body Weight Resistance Exercise vs. Treadmill Running.

The aim of this study was to compare postexercise autonomic nervous system (ANS) recovery between a high-intensity training protocol (HITP) and high-intensity treadmill running (TM) in 10 physically fit males. For each trial, ANS activity was measured through the heart rate variability markers of log-transformed square root of the successive R-R differences (lnRMSSD) and high frequency power (lnHF). These markers were analyzed in 5-minute segments at 5-10 minutes of the pre-exercise period (PRE) and during the postexercise period at 15-20 minutes (POST15-20min), 20-25 minutes (POST20-25min), 25-30 minutes (POST25-30min), and 1 hour (POST60min). Plasma epinephrine (E) and norepinephrine (NE) were also examined at PRE, immediately post exercise (IPE), 1-hour post (1HP), and 2-hour post (2HP). The results of this study demonstrate a significant overall time-dependent decreases in lnRMSSD and lnHF (p = 0.003 and 0.001, respectively) in both trials. Trial-dependent differences were also observed in postexercise lnRMSSD and lnHF measures, HITP being significantly lower than TM (p = 0.002 and 0.000, respectively). lnRMSSD at POST60min-HITP remained significantly lower compared to PRE (p ≤ 0.05). lnHF returned to baseline in HIPT and TM (p = 0.081 and 0.065, respectively). A time-dependent increase in E and NE was observed in both trials at time point IPE when compared to PRE (p ≤ 0.05). E at 1HP and 2HP returned to near resting levels (p = 0.62, p = 0.26), whereas NE remained slightly elevated in both groups (p = 0.003, p = 0.021). A trial-dependent increase was observed with the HITP eliciting a greater E response (p = 0.025) and NE response (p = 0.03). The HITP causes a greater disruption of the ANS than intensity-matched TM exercise.

Mechanisms of exercise-induced cardioprotection.

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.

Interleukin-6 mediates exercise preconditioning against myocardial ischemia reperfusion injury.

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 (Thr(202)/Tyr(204)) and p-p38 MAPK (Thr(180)/Tyr(182)) 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.

Histological and biochemical outcomes of cardiac pathology in mdx mice with dietary quercetin enrichment.

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 ß1 (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.

Involvement of the δ-opioid receptor in exercise-induced cardioprotection.

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 + Î´-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 < 0.001 and P = 0.003, respectively) compared with the Sham group, while the Ex group was partly protected. After IR, apoptosis was evident in Sed hearts (P = 0.016), while Ex and ExD hearts were protected. Data suggest that cardioprotective opioids are produced by the heart, but not by the soleus. After IR, the δ-opioid receptor may mediate, in part, cardioprotection against necrosis but not apoptosis.

Effects of Acute Sleep Deprivation on the Physiological Response to Woodsmoke and Exercise.

OBJECTIVE: To evaluate sleep deprivation effects on the acute physiological response to a combined stressor of woodsmoke and exercise. METHODS: Ten participants completed two exercise trials (8 hours of sleep vs 4 hours) with woodsmoke. Trials were conducted in a crossover design. Key measures examined before and after each trial included heart rate variability, pulse wave velocity, blood pressure, pulmonary function testing, and oxidative stress. RESULTS: Acute sleep deprivation experienced before exercise and woodsmoke exposure did not impact metrics of heart rate variability, pulse wave velocity, pulmonary function testing, blood pressure, or oxidative stress. CONCLUSIONS: Acute sleep deprivation did not amplify physiologic metrics in response to moderate-intensity aerobic exercise with inhaled woodsmoke. Although findings do not eliminate the negative impacts of inhaling woodsmoke, more research is needed to understand the acute effects of woodsmoke exposure on the cardiovascular system. 1.

Blood oxidative-stress markers during a high-altitude trek.

UNLABELLED: Oxidative stress occurs as a result of altitude-induced hypobaric hypoxia and physical exercise. The effect of exercise on oxidative stress under hypobaric hypoxia is not well understood. PURPOSE: To determine the effect of high-altitude exercise on blood oxidative stress. Nine male participants completed a 2-d trek up and down Mt Rainer, in North America, at a peak altitude of 4,393 m. Day 1 consisted of steady-pace climbing for 6.25 hr to a final elevation of 3,000 m. The 4,393-m summit was reached on Day 2 in approximately 5 hr. Climb-rest intervals varied but were consistent between participants, with approximately 14 hr of total time including rest periods. Blood samples were assayed for biomarkers of oxidative stress and antioxidant potential at the following time points: Pre (before the trek), 3Kup (at ascent to 3,000 m), 3Kdown (at 3,000 m on the descent), and Post (posttrek at base elevation). Blood serum variables included ferric-reducing antioxidant potential (FRAP), Trolox equivalent antioxidant capacity (TEAC), protein carbonyls (PC), and lipid hydroperoxides. Serum FRAP was elevated at 3Kup and 3Kdown compared with Pre and Post values (p = .004, 8% and 11% increase from Pre). Serum TEAC values were increased at 3Kdown and Post (p = .032, 10% and 18% increase from Pre). Serum PC were elevated at 3Kup and 3Kdown time points (p = .034, 194% and 138% increase from Pre), while lipid hydroperoxides were elevated Post only (p = .004, 257% increase from Pre). CONCLUSIONS: Findings indicate that high-altitude trekking is associated with increased blood oxidative stress.

Hybrid and Traditional Cardiac Rehabilitation in a Rural Area: A RETROSPECTIVE STUDY.

PURPOSE: Cardiac rehabilitation is a prescribed exercise intervention that reduces cardiovascular mortality, secondary events, and hospitalizations. Hybrid cardiac rehabilitation (HBCR) is an alternative method that overcomes barriers to participation, such as travel distance and transportation issues. To date, comparisons of HBCR and traditional cardiac rehabilitation (TCR) are limited to randomized controlled trials, which may influence outcomes due to supervision associated with clinical research. Coincidental to the COVID-19 pandemic, we investigated HBCR effectiveness (peak metabolic equivalents [peak METs]), resting heart rate (RHR), resting systolic (SBP) and diastolic blood pressure (DBP), body mass index (BMI), and depression outcomes (Patient Health Questionnaire-9 [PHQ-9]). METHODS: Via retrospective analysis, TCR and HBCR were examined during the COVID-19 pandemic (October 1, 2020, and March 31, 2022). Key dependent variables were quantified at baseline (pre) and discharge (post). Completion was determined by participation in 18 monitored TCR exercise sessions and four monitored HBCR exercise sessions. RESULTS: Peak METs increased at post-TCR and HBCR ( P < .001); however, TCR resulted in greater improvements ( P = .034). The PHQ-9 scores were decreased in all groups ( P < .001), while post-SBP and BMI did not improve (SBP: P = .185, BMI: P = .355). Post-DBP and RHR increased (DBP: P = .003, RHR: P = .032), although associations between intervention and program completion were not observed ( P = .172). CONCLUSIONS: Peak METs and depression metric outcomes (PHQ-9) improved with TCR and HBCR. Improvements in exercise capacity were greater with TCR; however, HBCR did not produce inferior results by comparison, an outcome that may have been essential during the first 18 mo of the COVID-19 pandemic.

Indicators of increased ER stress and UPR in aged D2-mdx and human dystrophic skeletal muscles.

Duchenne muscular dystrophy (DMD) is a progressive muscle disease that results in muscle wasting, wheelchair dependence, and eventual death due to cardiac and respiratory complications. In addition to muscle fragility, dystrophin deficiency also results in multiple secondary dysfunctions, which may lead to the accumulation of unfolded proteins causing endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). The purpose of this investigation was to understand how ER stress and the UPR are modified in muscle from D2-mdx mice, an emerging DMD model, and from humans with DMD. We hypothesized that markers of ER stress and the UPR are upregulated in D2-mdx and human dystrophic muscles compared to their healthy counterparts. Immunoblotting in diaphragms from 11-month-old D2-mdx and DBA mice indicated increased ER stress and UPR in dystrophic diaphragms compared to healthy, including increased relative abundance of ER stress chaperone CHOP, canonical ER stress transducers ATF6 and pIRE1α S724, and transcription factors that regulate the UPR such as ATF4, XBP1s, and peIF2α S51. The publicly available Affymetrix dataset (GSE38417) was used to analyze the expression of ER stress and UPR-related transcripts and processes. Fifty-eight upregulated genes related to ER stress and the UPR in human dystrophic muscles suggest pathway activation. Further, based on analyses using iRegulon, putative transcription factors that regulate this upregulation profile were identified, including ATF6, XBP1, ATF4, CREB3L2, and EIF2AK3. This study adds to and extends the emerging knowledge of ER stress and the UPR in dystrophin deficiency and identifies transcriptional regulators that may be responsible for these changes and be of therapeutic interest.

Training in a Hot Environment Fails to Elicit Changes in the Blood Oxidative Stress Response.

Environmental temperature can impact exercise-induced blood oxidative stress; however, the effects of heat acclimation on this response have not been fully elucidated. The purpose of the study was to investigate the effects of hot (33°C) and room temperature (20°C) environments on post-exercise blood oxidative stress responses following 15 temperature acclimation sessions. Untrained participants (n = 38, 26 ± 7 years, VO2peak = 38.0 ± 7.2 years) completed 15 temperature acclimation sessions of a cycling bout at an intensity perceived as "hard" in either a hot (33°C) or room temperature (20°C) environment. Pre and post acclimation exercise tolerance trials were conducted, which involved cycling at 50% Wpeak for one hour. Blood sampling occurred before exercise, immediately after, two hours, and four hours after the exercise tolerance trials. Blood samples were analyzed for oxidative stress markers including lipid hydroperoxides, 8-isoprostanes, protein carbonyls, 3-nitrotyrosine, ferric-reducing ability of plasma, and Trolox-equivalent antioxidant capacity. Exercise-dependent increases were observed in lipid hydroperoxides, Trolox-equivalent antioxidant capacity, and ferric-reducing ability of plasma (p < 0.001). Considering exercise-induced elevations in markers of blood oxidative stress, there were no differences observed between environmental temperatures before or after the acclimation training period.

Cardiac Rehabilitation and Resting Blood Pressure: MONTANA OUTCOMES PROJECT CARDIAC REHABILITATION REGISTRY FINDINGS.

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.

Application of a Novel Collection of Exhaled Breath Condensate to Exercise Settings.

The collection of exhaled breath condensate (EBC) is a non-invasive method for obtaining biosamples from the lower respiratory tract, an approach amenable to exercise, environmental, and work physiology applications. The purpose of this study was to develop a cost-effective, reproducible methodology for obtaining larger volume EBC samples. Participants (male: n = 10; female: n = 6; 26 ± 8 yrs.) completed a 10 min EBC collection using a novel device (N-EBC). After initial collection, a 45 min bout of cycling at 75% HRmax was performed, followed by another N-EBC collection. In a subset of individuals (n = 5), EBC was obtained using both the novel technique and a commercially available EBC collection device (R-EBC) in a randomized fashion. N-EBC volume-pre- and post-exercise (2.3 ± 0.8 and 2.6 ± 0.9 mL, respectively)-and pH (7.4 ± 0.5 and 7.4 ± 0.5, respectively) were not significantly different. When normalized for participant body height, device comparisons indicated N-EBC volumes were larger than R-EBC at pre-exercise (+12%) and post-exercise (+48%). Following moderate-intensity exercise, no changes in the pre- and post-trial values of Pentraxin 3 (0.25 ± 0.04 and 0.26 ± 0.06 pg/mL, respectively) and 8-Isoprostrane (0.43 ± 0.33 and 0.36 ± 0.24 pg/mL, respectively) concentrations were observed. In a cost-efficient fashion, the N-EBC method produced larger sample volumes, both pre- and post-exercise, facilitating more biomarker tests to be performed.