Autophagy in the heart is enhanced and independent of disease progression in mus musculus dystrophinopathy models

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

Successive Bouts of Cycling Stimulates Genes Associated with Mitochondrial Biogenesis

Exercise increases mRNA for genes involved in mitochondrial biogenesis and oxidative enzyme capacity. However, little is known about how these genes respond to consecutive bouts of prolonged exercise. We examined the effects of 3 h of intensive cycling performed on three consecutive days on the mRNA associated with mitochondrial biogenesis in trained human subjects. Forty trained cyclists were tested for VO2max (54.7 ± 1.1 ml kg−1 min−1). The subjects cycled at 57% wattsmax for 3 h using their own bicycles on CompuTrainer™ Pro Model trainers (RacerMate, Seattle, WA) on three consecutive days. Muscle biopsies were obtained from the vastus lateralis pre- and post-exercise on days one and three. Muscle samples were analyzed for mRNA content of peroxisome proliferator receptor gamma coactivator-1 alpha (PGC-1α), sirtuin 1 (Sirt-1), cytochrome c, and citrate synthase. Data were analyzed using a 2 (time) × 2 (day) repeated measures ANOVA. Of the mRNA analyzed, the following increased from pre to post 3 h rides: cytochrome c (P = 0.006), citrate synthase (P = 0.03), PGC-1α (P \u3c 0.001), and Sirt-1 (P = 0.005). The following mRNA showed significant effects from days one to three: cytochrome c (P \u3c 0.001) and citrate synthase (P = 0.01). These data show that exhaustive cycling performed on three consecutive days resulted in both acute and chronic stimuli for mRNA associated with mitochondrial biogenesis in already trained subjects. This is the first study to illustrate an increase in sirtuin-1 mRNA with acute and chronic exercise. These data contribute to the understanding of mRNA expression during both acute and successive bouts of prolonged exercise

Quercetin Ingestion Does Not Alter Cytokine Changes in Athletes Competing in the Western States Endurance Run

The purpose of this study was to measure the influence of quercetin on plasma cytokines, leukocyte cytokine mRNA, and related variables in ultramarathoners competing in the 160-km Western States Endurance Run (WSER). Sixty-three runners were randomized to quercetin and placebo groups and under double-blinded methods ingested 1000 mg/day quercetin for 3 weeks before the WSER. Thirty-nine of the 63 subjects (n = 18 for quercetin, n = 21 for placebo) finished the race and provided blood samples the morning before the race and 15–30 min postrace. Significant prerace to postrace WSER increases were measured for nine proinflammatory and anti-inflammatory plasma cytokines, cortisol (quercetin = 94%, placebo = 96%), serum C-reactive protein (CRP) (mean ± SE absolute increase, quercetin = 31.8 ± 4.2, placebo = 38.2 ± 5.0 mg/L), and creatine kinase (CK) (quercetin = 21,575 ± 3,977, placebo = 19,455 ± 3,969 U/L), with no significant group differences. Interleukin-6 (IL-6) mRNA did not change post-WSER, with a significant decrease measured for leukocyte IL-8 mRNA (0.21 ± 0.03-fold and 0.25 ± 0.04-fold change from rest, quercetin and placebo, respectively) and significant increases for IL-1Ra mRNA (1.43 ± 0.18-fold and 1.40 ± 0.16-fold change, quercetin and placebo, respectively) and IL-10 mRNA (12.9 ± 3.9-fold and 17.2 ± 6.1-fold change, quercetin and placebo, respectively), with no significant differences between groups. In conclusion, quercetin ingestion (1 g/day) by ultramarathon athletes for 3 weeks before a competitive 160-km race significantly increased plasma quercetin levels but failed to attenuate muscle damage, inflammation, increases in plasma cytokine and hormone levels, and alterations in leukocyte cytokine mRNA expression

Clinical practice guidelines of remote ischemic conditioning for the management of cerebrovascular diseases

Remote ischemic conditioning (RIC) using transient limb ischemia and reperfusion has been shown in small clinical studies to reduce myocardial injury and infarction in cardiac patients, although larger clinical outcome studies have been neutral. Experimental and emerging clinical studies have also reported beneficial effects of limb RIC in a number of different settings of cerebrovascular disease including stroke (ischemic and hemorrhagic), carotid artery stenosis, intracranial artery stenosis, aneurysms, small vessel disease, and vascular cognitive impairment. Although limb RIC has many advantages, in that it is non-invasive, easy to administer, relatively innocuous, cost-effective, has few or no contraindications, and may be deployed under various circumstances (e.g., home, ambulance, and hospital), several questions remain regarding its clinical application for cerebrovascular disease. Therefore, in this document, we aim to provide practicing clinicians with a coherent synthesis of the latest scientific evidence, and we propose several recommendations to help facilitate the clinical application of limb RIC for the management of cerebrovascular disease

Why Does Exercise “Triggerâ€? Adaptive Protective Responses in the Heart?

Numerous epidemiological studies suggest that individuals who exercise have decreased cardiac morbidity and mortality. Pre-clinical studies in animal models also find clear cardioprotective phenotypes in animals that exercise, specifically characterized by lower myocardial infarction and arrhythmia. Despite the clear benefits, the underlying cellular and molecular mechanisms that are responsible for exercise preconditioning are not fully understood. In particular, the adaptive signaling events that occur during exercise to “trigger� cardioprotection represent emerging paradigms. In this review, we discuss recent studies that have identified several different factors that appear to initiate exercise preconditioning. We summarize the evidence for and against specific cellular factors in triggering exercise adaptations and identify areas for future study

Inflammatory responses to acute exercise during pulmonary rehabilitation in patients with COPD

Objective Pulmonary rehabilitation is a cornerstone treatment in the management of chronic obstructive pulmonary disease (COPD). Acute bouts of exercise can lead to short bursts of inflammation in healthy individuals. However, it is unclear how COPD patients respond to acute bouts of exercise. This study assessed inflammatory responses to exercise in COPD patients at the start (phase 1) and end (phase 2) of pulmonary rehabilitation. Methods Blood samples were collected before and after an acute exercise bout at the start (phase 1, n = 40) and end (phase 2, n = 27) of pulmonary rehabilitation. The primary outcome was change in fibrinogen concentrations. Secondary outcomes were changes in CRP concentrations, total/differential leukocyte counts, markers of neutrophil activation (CD11b, CD62L and CD66b), and neutrophil subsets (mature, suppressive, immature, progenitor). Results Acute exercise (phase 1) did not induce significant changes in fibrinogen (p = 0.242) or CRP (p = 0.476). Total leukocyte count [mean difference (MD), 0.5 ± 1.1 (109 L−1); p = 0.004], neutrophil count [MD, 0.4 ± 0.8 (109 L−1); p < 0.001], and immature neutrophils (MD, 0.6 ± 0.8%; p < 0.001) increased post-exercise. Neutrophil activation markers, CD11b (p = 0.470), CD66b (p = 0.334), and CD62L (p = 0.352) were not significantly altered post-exercise. In comparison to the start of pulmonary rehabilitation (phase 2), acute exercise at the end of pulmonary rehabilitation led to a greater fibrinogen response (MD, 84 mg/dL (95% CI − 14, 182); p = 0.045). Conclusion An acute bout of exercise does not appear to induce significant alterations in the concentrations of inflammatory mediators but can increase white blood cell subsets post-exercise. A greater fibrinogen response to acute exercise is seen at the end of pulmonary rehabilitation when compared to the start. Further research is required to understand the clinical context of these acute inflammatory responses to exercise

A self-adaptive boundary search genetic algorithm and its application to water distribution systems

The success of the application of genetic algorithms (GA) or evolutionary optimization methods to the design and rehabilitation of water distribution systems has been shown to be an innovative approach for the water industry. The optimal design and rehabilitation of water distribution systems is a constrained non-linear optimization problem. Constraints (for example, the minimum pressure requirements) are generally handled within genetic algorithm optimization by introducing a penalty cost function. The optimal or near optimal solution is found when the pressures at some nodes are close to the minimum required pressure or at the boundary of critical constraints. This paper presents a new approach called the self-adaptive boundary search strategy for selection of penalty factor within genetic algorithm optimization. The approach co-evolves and self-adapts the penalty factor such that the genetic algorithm search is guided towards and preserved around constraint boundaries. Thus it reduces the amount of simulation computations within the GA search and enhances the efficacy at reaching the optimal or near optimal solution. To demonstrate its effectiveness, the self-adaptive boundary search strategy is applied to a case study of the optimization of a water distribution system in this paper. It has been shown that the boundary GA search strategy is effective at adapting the feasibility of GA populations for a wide range of penalty factors. As a consequence, the boundary GA has been able to successfully find the least cost solution in the case study more effectively than a GA without the boundary search strategy. Thus a reliable least cost solution is guaranteed for the GA optimization of a water distribution system.Wu, Zheng Y.; Simpson, Angus

MUSCLE SORENESS AND DAMAGE DURING WILDLAND FIREFIGHTER CRITICAL TRAINING

K. Christison, S. Gurney, C. Williamson-Reisdorph, T. Quindry, J. Sol, K. Tiemessen, C. Palmer, M. Bundle, J. Quindry, FACSM, C. Dumke, FACSM University of Montana, Missoula, MT Wildland firefighters (WLFF) undergo a critical training (CT) period immediately prior to the firefighting season. The intensive nature of preparatory CT exercise regimen could lead to muscle damage, as previously reported cases of rhabdomyolysis in WLFF have been documented. PURPOSE: To establish the effects of a two-week critical training period on acute markers of muscle damage in WLFF. METHODS: Eighteen male (29.4±1.1 years, 182.1±1.6 cm) and three female (26.7±2.6 years, 169.5±4.2 cm) Type I Interagency Hotshot (IHC) WLFF were studied during a 13-day critical training period. Daily body weight (BW), upper body (US), and lower body (LS) muscle soreness scales were collected. Venous blood was collected from the antecubital region on Days 1, 4, 8, and 11 to measure creatine kinase (CK) and lactate dehydrogenase (LDH). Skin fold measurements were taken on Day 1 and Day 11 to calculate body fat (BF). Fitness was assessed by the BLM fitness challenge (pushups, pullups, situps, 1.5-mile run). One- way repeated measures ANOVA were used to analyze CK, LDH, US, and LS. Paired samples t-tests were used to identify differences in BW and BF. Data presented as mean±SEM. RESULTS: No differences in body weight were observed between Day 1 and 11 (p=0.065). BF significantly decreased from Day 1 and 1 (15.3±1.4% vs. 14.1±1.3%, p=0.002). US and LS showed a main effect of time, elevated from baseline for subsequent days, with a peak on Day 3 (US: 3.8±0.5 cm, p\u3c0.001; LS: 4.3±0.3 cm, p\u3c0.001). CK showed a significant effect of time, elevated from baseline, with a peak on Day 4 (73.4±14.4 U·L-1 vs. 132.8±15.4 U·L-1, p=0.001). LDH showed a significant effect of time, where Day 11 significantly increased from Day 1 (159.4±5.5 IU·L-1 vs.164.4±6.9 IU·L-1, p=0.04). Fitness was negatively correlated with the change in muscle soreness from baseline to peak (r=-0.72, p=0.013). CONCLUSION: These data suggest that WLFF undergo significant physiological stressors that result in muscle soreness and damage during CT. Fitness appears to attenuate the soreness induced by CT. Careful preparation and monitoring of the training stimulus is key to avoid clinical ramifications. Funded by the USFS 16-CR-11138200-005