Characterisation of phenotypic patterns in equine exercise-associated myopathies.

BACKGROUND: Equine exercise-associated myopathies are prevalent, clinically heterogeneous, generally idiopathic disorders characterised by episodes of myofibre damage that occur in association with exercise. Episodes are intermittent and vary within and between affected horses and across breeds. The aetiopathogenesis is often unclear; there might be multiple causes. Poor phenotypic characterisation hinders genetic and other disease analyses. OBJECTIVES: The aim of this study was to characterise phenotypic patterns across exercise-associated myopathies in horses. STUDY DESIGN: Historical cross-sectional study, with subsequent masked case-control validation study. METHODS: Historical clinical and histological features from muscle samples (n = 109) were used for k-means clustering and validated using principal components analysis and hierarchical clustering. For further validation, a blinded histological study (69 horses) was conducted comparing two phenotypic groups with selected controls and horses with histopathological features characterised by myofibrillar disruption. RESULTS: We identified two distinct broad phenotypes: a non-classic exercise-associated myopathy syndrome (EAMS) subtype was associated with practitioner-described signs of apparent muscle pain (p < 0.001), reluctance to move (10.85, p = 0.001), abnormal gait (p < 0.001), ataxia (p = 0.001) and paresis (p = 0.001); while a non-specific classic RER subtype was not uniquely associated with any particular variables. No histological differences were identified between subtypes in the validation study, and no identifying histopathological features for other equine myopathies identified in either subtype. MAIN LIMITATIONS: Lack of an independent validation population; small sample size of smaller identified subtypes; lack of positive control myofibrillar myopathy cases; case descriptions derived from multiple independent and unblinded practitioners. CONCLUSIONS: This is the first study using computational clustering methods to identify phenotypic patterns in equine exercise-associated myopathies, and suggests that differences in patterns of presenting clinical signs support multiple disease subtypes, with EAMS a novel subtype not previously described. Routine muscle histopathology was not helpful in sub-categorising the phenotypes in our population.

CONTEXTE: Les myopathies induites à l'exercice demeurent fréquentes, hétérogènes cliniquement et représentent des désordres idiopathiques caractérisés par des épisodes de dommages myofibrillaires en lien avec l'exercice. Les épisodes sont intermittents et varient à la fois chez le même cheval, entre chevaux et entre les différentes races. L'étiopathogénie demeure obscure et pourrait être multifactorielle. La pauvre caractérisation phénotypique des myopathies ne simplifie pas les analyses génétiques ni celles d'autres maladies. OBJECTIFS: Le but de cette étude est de caractériser les patrons phénotypiques en lien avec les myopathies induites à l'exercice chez le cheval. TYPE D'ÉTUDE: Étude transversale historique et étude subséquente de validation de cas témoins aveugle. MÉTHODES: Les facteurs clés cliniques et histologiques provenant d'échantillons de muscles (n = 109) ont été utilisés pour l'algorithme de K­moyennes et validés par le biais d'analyse des composantes principales et de classification hiérarchique. Pour validation additionnelle, une étude histologique à l'aveugle (69 chevaux) a été faite comparant les deux groupes phénotypiques avec des contrôles sélectionnés et des chevaux avec éléments histopathologiques caractérisés par de la discontinuité myofibrillaire. RÉSULTATS: Deux phénotypes distincts ont été identifiés: un premier sous­type de syndrome de myopathie induite à l'exercice non­classique (EAMS) associé à de la douleur musculaire telle que décrite par le praticien suivant le cheval (χ2 (df=1,n=109) = 19.33, p < 0.001), difficulté à se déplacer (χ2 (df=1,n=109) = 10.85, p = 0.001), démarche anormale (χ2 (df=1,n=109) = 34.61, p < 0.001), ataxie (χ2 (df=1,n=109) = 10.88, p = 0.001) et parésie (χ2 (df=1,n=109) = 10.88, p = 0.001); alors qu'un sous­type RER classique non­spécifique n'était associé à aucune variable en particulier. Aucune différente histologique n'a été identifié entre les sous­types dans l'étude de validation et aucune caractéristique histopathologique d'autres myopathies équines n'a été identifiées dans les différents sous­types. LIMITES PRINCIPALES: Aucune population indépendante pour validation; petite taille d'échantillon pour les sous­types peu nombreux identifiés; aucun cas contrôles positifs de myopathie fibrillaire; description des cas provenant de multiples praticiens indépendants et non­aveugles. CONCLUSION: Cette étude est la première utilisant des méthodes de regroupement informatique pour identifier des patrons phénotypiques de myopathies équines induites à l'exercice et suggère que des différences existent dans les patrons de signes cliniques en faveur de multiples sous­types de maladie, incluant EAMS qui représente un nouveau sous­type non décrit jusqu'à maintenant. L'histopathologie musculaire de routine n'a pas permis de sous­catégoriser les phénotypes dans cette population.

The putative prenyltransferase Nus1 is required for filamentation in the human fungal pathogen Candida albicans.

Candida albicans is a major fungal pathogen of humans that can cause serious systemic infections in vulnerable immunocompromised populations. One of its virulence attributes is its capacity to transition between yeast and filamentous morphologies, but our understanding of this process remains incomplete. Here, we analyzed data from a functional genomic screen performed with the C. albicans Gene Replacement And Conditional Expression collection to identify genes crucial for morphogenesis in host-relevant conditions. Through manual scoring of microscopy images coupled with analysis of each image using a deep learning-based method termed Candescence, we identified 307 genes important for filamentation in tissue culture medium at 37°C with 5% CO2. One such factor was orf19.5963, which is predicted to encode the prenyltransferase Nus1 based on sequence homology to Saccharomyces cerevisiae. We further showed that Nus1 and its predicted interacting partner Rer2 are important for filamentation in multiple liquid filament-inducing conditions as well as for wrinkly colony formation on solid agar. Finally, we highlight that Nus1 and Rer2 likely govern C. albicans morphogenesis due to their importance in intracellular trafficking, as well as maintaining lipid homeostasis. Overall, this work identifies Nus1 and Rer2 as important regulators of C. albicans filamentation and highlights the power of functional genomic screens in advancing our understanding of gene function in human fungal pathogens.

Respiratory exchange ratio overshoot during exercise recovery: a promising prognostic marker in HFrEF.

BACKGROUND AND AIMS: Transient increases (overshoot) in respiratory gas analyses have been observed during exercise recovery, but their clinical significance is not clearly understood. An overshoot phenomenon of the respiratory exchange ratio (RER) is commonly observed during recovery from maximal cardiopulmonary exercise testing (CPET), but it has been found reduced in patients with heart failure with reduced ejection fraction (HFrEF). The aim of the study was to analyze the clinical significance of these RER recovery parameters and to understand if these may improve the risk stratification of patients with HFrEF. METHODS: This cross-sectional study includes HFrEF patients who underwent functional evaluation with maximal CPET for the heart transplant checklist at our Sports and Exercise Medicine Division. RER recovery parameters, including RER overshoot as the percentual increase of RER during recovery (RER mag), have been evaluated after CPET with assessment of hard clinical long-term endpoints (MACEs/deaths and transplant/LVAD-free survival). RESULTS: A total of 190 patients with HFrEF and 103 controls were included (54.6 ± 11.9 years; 73% male). RER recovery parameters were significantly lower in patients with HFrEF compared to healthy subjects (RER mag 24.8 ± 14.5% vs 31.4 ± 13.0%), and they showed significant correlations with prognostically relevant CPET parameters. Thirty-three patients with HFrEF did not present a RER overshoot, showing worse cardiorespiratory fitness and efficiency when compared with those patients who showed a detectable overshoot (VO2 peak: 11.0 ± 3.1 vs 15.9 ± 5.1 ml/kg/min; VE/VCO2 slope: 41.5 ± 8.7 vs 32.9 ± 7.9; ΔPETCO2: 2.75 ± 1.83 vs 4.45 ± 2.69 mmHg, respectively). The presence of RER overshoot was associated with a lower risk of cardiovascular events and longer transplant-free survival. CONCLUSION: RER overshoot represents a meaningful cardiorespiratory index to monitor during exercise gas exchange evaluation; it is an easily detectable parameter that could support clinicians to comprehensively interpreting patients' functional impairment and prognosis. CPET recovery analyses should be implemented in the clinical decision-making of advanced HF.

Degeneration of oil bodies by rough endoplasmic reticulum -associated protein during seed germination in Cannabis sativa.

Oil bodies serve as a vital energy source of embryos during germination and contribute to sustaining the initial growth of seedlings until photosynthesis initiation. Despite high stability in chemical properties, how oil bodies break down and go into the degradation process during germination is still unknown. This study provides a morphological understanding of the mobilization of stored compounds in the seed germination of Cannabis. The achenes of fibrous hemp cultivar (Cannabis sativa cv. 'Chungsam') were examined in this study using light microscopy, scanning electron microscopy and transmission electron microscopy. Oil bodies in Cannabis seeds appeared spherical and sporadically distributed in the cotyledonary cells. Protein bodies contained electron-dense globoid and heterogeneous protein matrices. During seed germination, rough endoplasmic reticulum (rER) and high electron-dense substances were present adjacent to the oil bodies. The border of the oil bodies became a dense cluster region and appeared as a sinuous outline. Later, irregular hyaline areas were distributed throughout oil bodies, showing the destabilized emulsification of oil bodies. Finally, the oil bodies lost their morphology and fused with each other. The storage proteins were concentrated in the centre of the protein body as a dense homogenous circular mass surrounded by a light heterogeneous area. Some storage proteins are considered emulsifying agents on the surface region of oil bodies, enabling them to remain stable and distinct within and outside cotyledon cells. At the early germination stage, rER appeared and dense substances aggregated adjacent to the oil bodies. Certain proteins were synthesized within the rER and then translocated into the oil bodies by crossing the half membrane of oil bodies. Our data suggest that rER-associated proteins function as enzymes to lyse the emulsifying proteins, thereby weakening the emulsifying agent on the surface of the oil bodies. This process plays a key role in the degeneration of oil bodies and induces coalescence during seed germination.

Glucocorticoid enhances presenilin1-dependent Aß production at ER's mitochondrial-associated membrane by downregulating Rer1 in neuronal cells.

Stress-induced release of glucocorticoid is an important amyloidogenic factor that upregulates amyloid precursor protein (APP) and ß secretase 1 (BACE1) levels. Glucocorticoid also contributes to the pathogenesis of Alzheimer's disease (AD) by increasing ER-mitochondria connectivity, in which amyloid ß (Aß) processing occurs rigorously because of its lipid raft-rich characteristics. However, the mechanism by which glucocorticoid enhances γ-secretase activity in the mitochondrial-associated membrane of ER (MAM) and subsequent accumulation of mitochondrial Aß is unclear. In this study, we determined how glucocorticoid enhances Aß production in MAM using SH-SY5Y cells and ICR mice. First, we observed that cortisol-induced Aß accumulation in mitochondria preceded its extracellular apposition by enhancing γ-secretase activity, which was the result of increased presenilin 1 (PSEN1) localization in MAM. Screening data revealed that cortisol selectively downregulated the ER retrieval protein Rer1, which triggered its maturation and subsequent entry into the endocytic secretory pathway of PSEN1. Accordingly, overexpression of RER1 reversed the deleterious effects of mitochondrial Aß on mitochondrial respiratory function and neuronal cell viability. Notably, we found that cortisol guided the glucocorticoid receptor (GR) to bind directly to the RER1 promoter, thus trans-repressing its expression. Inhibiting GR function reduced Aß accumulation at mitochondria and improved the outcome of a spatial memory task in mice exposed to corticosterone. Taken together, glucocorticoid enhances PSEN1-mediated Aß generation at MAM by downregulating Rer1, which is a potential target at early stages of AD pathogenesis.

Loss of Brain Angiogenesis Inhibitor-3 (BAI3) G-Protein Coupled Receptor in Mice Regulates Adaptive Thermogenesis by Enhancing Energy Expenditure.

Effective energy expenditure is critical for maintaining body weight (BW). However, underlying mechanisms contributing to increased BW remain unknown. We characterized the role of brain angiogenesis inhibitor-3 (BAI3/ADGRB3), an adhesion G-protein coupled receptor (aGPCR), in regulating BW. A CRISPR/Cas9 gene editing approach was utilized to generate a whole-body deletion of the BAI3 gene (BAI3-/-). In both BAI3-/- male and female mice, a significant reduction in BW was observed compared to BAI3+/+ control mice. Quantitative magnetic imaging analysis showed that lean and fat masses were reduced in male and female mice with BAI3 deficiency. Total activity, food intake, energy expenditure (EE), and respiratory exchange ratio (RER) were assessed in mice housed at room temperature using a Comprehensive Lab Animal Monitoring System (CLAMS). While no differences were observed in the activity between the two genotypes in male or female mice, energy expenditure was increased in both sexes with BAI3 deficiency. However, at thermoneutrality (30 °C), no differences in energy expenditure were observed between the two genotypes for either sex, suggesting a role for BAI3 in adaptive thermogenesis. Notably, in male BAI3-/- mice, food intake was reduced, and RER was increased, but these attributes remained unchanged in the female mice upon BAI3 loss. Gene expression analysis showed increased mRNA abundance of thermogenic genes Ucp1, Pgc1α, Prdm16, and Elov3 in brown adipose tissue (BAT). These outcomes suggest that adaptive thermogenesis due to enhanced BAT activity contributes to increased energy expenditure and reduced BW with BAI3 deficiency. Additionally, sex-dependent differences were observed in food intake and RER. These studies identify BAI3 as a novel regulator of BW that can be potentially targeted to improve whole-body energy expenditure.

Respiratory gas kinetics in patients with congestive heart failure during recovery from peak exercise.

BACKGROUND: Cardiopulmonary Exercise Testing (CPX) is essential for the assessment of exercise capacity for patients with Chronic Heart Failure (CHF). Respiratory gas and hemodynamic parameters such as Ventilatory Efficiency (VE/VCO2 slope), peak oxygen uptake (peak VO2), and heart rate recovery are established diagnostic and prognostic markers for clinical populations. Previous studies have suggested the clinical value of metrics related to respiratory gas collected during recovery from peak exercise, particularly recovery time to 50% (T1/2) of peak VO2. The current study explores these metrics in detail during recovery from peak exercise in CHF. METHODS: Patients with CHF who were referred for CPX and healthy individuals without formal diagnoses were assessed for inclusion. All subjects performed CPX on cycle ergometers to volitional exhaustion and were monitored for at least five minutes of recovery. CPX data were analyzed for overshoot of respiratory exchange ratio (RER=VCO2/VO2), ventilatory equivalent for oxygen (VE/VO2), end-tidal partial pressure of oxygen (PETO2), and T1/2 of peak VO2 and VCO2. RESULTS: Thirty-two patients with CHF and 30 controls were included. Peak VO2 differed significantly between patients and controls (13.5 ± 3.8 vs. 32.5 ± 9.8 mL/Kg*min-1, p < 0.001). Mean Left Ventricular Ejection Fraction (LVEF) was 35.9 ± 9.8% for patients with CHF compared to 61.1 ± 8.2% in the control group. The T1/2 of VO2, VCO2 and VE was significantly higher in patients (111.3 ± 51.0, 132.0 ± 38.8 and 155.6 ± 45.5s) than in controls (58.08 ± 13.2, 74.3 ± 21.1, 96.7 ± 36.8s; p < 0.001) while the overshoot of PETO2, VE/VO2 and RER was significantly lower in patients (7.2 ± 3.3, 41.9 ± 29.1 and 25.0 ± 13.6%) than in controls (10.1 ± 4.6, 62.1 ± 17.7 and 38.7 ± 15.1%; all p < 0.01). Most of the recovery metrics were significantly correlated with peak VO2 in CHF patients, but not with LVEF. CONCLUSIONS: Patients with CHF have a significantly blunted recovery from peak exercise. This is reflected in delays of VO2, VCO2, VE, PETO2, RER and VE/VO2, reflecting a greater energy required to return to baseline. Abnormal respiratory gas kinetics in CHF was negatively correlated with peak VO2 but not baseline LVEF.

Effect of early vs. late time-restricted high-fat feeding on circadian metabolism and weight loss in obese mice.

Time-restricted feeding (TRF) limits the time and duration of food availability without calorie reduction. Although a high-fat (HF) diet leads to disrupted circadian rhythms, TRF can prevent metabolic diseases, emphasizing the importance of the timing component. However, the question of when to implement the feeding window and its metabolic effect remains unclear, specifically in obese and metabolically impaired animals. Our aim was to study the effect of early vs. late TRF-HF on diet-induced obese mice in an 8:16 light-dark cycle. C57BL male mice were fed ad libitum a high-fat diet for 14 weeks after which they were given the same food during the early (E-TRF-HF) or late (L-TRF-HF) 8 h of the dark phase for 5 weeks. The control groups were fed ad libitum either a high-fat (AL-HF) or a low-fat diet (AL-LF). Respiratory exchange ratio (RER) was highest for the AL-LF group and the lowest for the AL-HF group. E-TRF-HF led to lower body weight and fat depots, lower glucose, C-peptide, insulin, cholesterol, leptin, TNFα, and ALT levels compared with L-TRF-HF- and AL-HF-fed mice. TRF-HF regardless whether it was early or late led to reduced inflammation and fat accumulation compared with AL-HF-fed mice. E-TRF-HF led to advanced liver circadian rhythms with higher amplitudes and daily expression levels of clock proteins. In addition, TRF-HF led to improved metabolic state in muscle and adipose tissue. In summary, E-TRF-HF leads to increased insulin sensitivity and fat oxidation and decreased body weight, fat profile and inflammation contrary to AL-HF-fed, but comparable to AL-LF-fed mice. These results emphasize the importance of timed feeding compared to ad libitum feeding, specifically to the early hours of the activity period.

Overshoot of the Respiratory Exchange Ratio during Recovery from Maximal Exercise Testing in Young Patients with Congenital Heart Disease.

INTRODUCTION: The overshoot of the respiratory exchange ratio (RER) after exercise is reduced in patients with heart failure. AIM: The present study aimed to investigate the presence of this phenomenon in young patients with congenital heart disease (CHD), who generally present reduced cardiorespiratory fitness. METHODS: In this retrospective study, patients with CHD underwent a maximal cardiopulmonary exercise testing (CPET) assessing the RER recovery parameters: the RER at peak exercise, the maximum RER value reached during recovery, the magnitude of the RER overshoot and the linear slope of the RER increase after the end of the exercise. RESULTS: In total, 117 patients were included in this study. Of these, there were 24 healthy age-matched control subjects and 93 young patients with CHD (transposition of great arteries, Fontan procedure, aortic coarctation and tetralogy of Fallot). All patients presented a RER overshoot during recovery. Patients with CHD showed reduced aerobic capacity and cardiorespiratory efficiency during exercise, as well as a lower RER overshoot when compared to controls. RER magnitude was higher in the controls and patients with aortic coarctation when compared to those with transposition of great arteries, previous Fontan procedure, and tetralogy of Fallot. The RER magnitude was found to be correlated with the most relevant cardiorespiratory fitness and efficiency indices. CONCLUSIONS: The present study proposes new recovery indices for functional evaluation in patients with CHD. Thus, the RER recovery overshoots analysis should be part of routine CPET evaluation to further improve prognostic risk stratifications in patients with CHD.

Does Caffeine Increase Fat Metabolism? A Systematic Review and Meta-Analysis.

Whether caffeine (CAF) increases fat metabolism remains debatable. Using systematic review coupled with meta-analysis, our aim was to determine effects of CAF on fat metabolism and the relevant factors moderating this effect. Electronic databases PubMed, SPORTDiscus, and Web of Science were searched using the following string: CAF AND (fat OR lipid) AND (metabolism OR oxidation). A meta-analytic approach aggregated data from 94 studies examining CAF's effect on fat metabolism assessed by different biomarkers. The overall effect size (ES) was 0.39 (95% confidence interval [CI] [0.30, 0.47], p < .001), indicating a small effect of CAF to increase fat metabolism; however, ES was significantly higher (p < .001) based on blood biomarkers (e.g., free fatty acids, glycerol) (ES = 0.55, 95% CI [0.43, 0.67]) versus expired gas analysis (respiratory exchange ratio, calculated fat oxidation) (ES = 0.26, 95% CI [0.16, 0.37]), although both were greater than zero. Fat metabolism increased to a greater extent (p = .02) during rest (ES = 0.51, 95% CI [0.41, 0.62]) versus exercise (ES = 0.35, 95% CI [0.26, 0.44]) across all studies, although ES was not different for studies reporting both conditions (ES = 0.49 and 0.44, respectively). There were no subgroup differences based on participants' fitness level, sex, or CAF dosage. CAF ingestion increases fat metabolism but is more consistent with blood biomarkers versus whole-body gas exchange measures. CAF has a small effect during rest across all studies, although similar to exercise when compared within the same study. CAF dosage did not moderate this effect.

Respiratory gas kinetics in patients with congestive heart failure during recovery from peak exercise

Abstract Background Cardiopulmonary Exercise Testing (CPX) is essential for the assessment of exercise capacity for patients with Chronic Heart Failure (CHF). Respiratory gas and hemodynamic parameters such as Ventilatory Efficiency (VE/VCO2 slope), peak oxygen uptake (peak VO2), and heart rate recovery are established diagnostic and prognostic markers for clinical populations. Previous studies have suggested the clinical value of metrics related to respiratory gas collected during recovery from peak exercise, particularly recovery time to 50% (T1/2) of peak VO2. The current study explores these metrics in detail during recovery from peak exercise in CHF. Methods Patients with CHF who were referred for CPX and healthy individuals without formal diagnoses were assessed for inclusion. All subjects performed CPX on cycle ergometers to volitional exhaustion and were monitored for at least five minutes of recovery. CPX data were analyzed for overshoot of respiratory exchange ratio (RER=VCO2/VO2), ventilatory equivalent for oxygen (VE/VO2), end-tidal partial pressure of oxygen (PETO2), and T1/2 of peak VO2 and VCO2. Results Thirty-two patients with CHF and 30 controls were included. Peak VO2 differed significantly between patients and controls (13.5 ± 3.8 vs. 32.5 ± 9.8 mL/Kg*min−1, p < 0.001). Mean Left Ventricular Ejection Fraction (LVEF) was 35.9 ± 9.8% for patients with CHF compared to 61.1 ± 8.2% in the control group. The T1/2 of VO2, VCO2 and VE was significantly higher in patients (111.3 ± 51.0, 132.0 ± 38.8 and 155.6 ± 45.5s) than in controls (58.08 ± 13.2, 74.3 ± 21.1, 96.7 ± 36.8s; p < 0.001) while the overshoot of PETO2, VE/VO2 and RER was significantly lower in patients (7.2 ± 3.3, 41.9 ± 29.1 and 25.0 ± 13.6%) than in controls (10.1 ± 4.6, 62.1 ± 17.7 and 38.7 ± 15.1%; all p < 0.01). Most of the recovery metrics were significantly correlated with peak VO2 in CHF patients, but not with LVEF. Conclusions Patients with CHF have a significantly blunted recovery from peak exercise. This is reflected in delays of VO2, VCO2, VE, PETO2, RER and VE/VO2, reflecting a greater energy required to return to baseline. Abnormal respiratory gas kinetics in CHF was negatively correlated with peak VO2 but not baseline LVEF.

A Cyclist on a Tricyclic: Exercise Intolerance Due to Chronotropic Incompetence.

Depression in athletes is prevalent, and antidepressant treatment may have a cardiovascular impact. We present a case, documented by serial exercise testing, of exertional intolerance due to chronotropic incompetence associated with tricyclic antidepressant use. This case underscores the importance of understanding the mechanism of action and side effects of antidepressants. (Level of Difficulty: Advanced.).

Weight interpretation of artificial neural network model for analysis of rice (Oryza sativa L.) with near-infrared spectroscopy.

Prediction models for major nutrients of rice were built using near-infrared (NIR) spectral data based on the artificial neural network (ANN). Scientific interpretation of the weight values was proposed and performed to understand the wavenumbers contributing to the prediction of nutrients. NIR spectra were acquired from 110 rice samples. Carbohydrate and moisture contents were predicted with values for the determination coefficient, relative root mean square error, range error ratio, and residual prediction deviation of 0.98, 0.11 %, 44, and 7.3, and 0.97, 0.80 %, 27, and 5.8, respectively. The results agreed well with ones reported in the previous studies and acquired by the conventional partial least squares (PLS)-variable importance in projection method. This study demonstrates that the combination of NIR and ANN is a powerful and accurate tool to monitor nutrients of rice and scientific interpretation of weights can be performed to overcome black box nature of the ANN.

A Cardiac Amino-Terminal GRK2 Peptide Inhibits Maladaptive Adipocyte Hypertrophy and Insulin Resistance During Diet-Induced Obesity.

Heart disease remains the leading cause of death, and mortality rates positively correlate with the presence of obesity and diabetes. Despite the correlation between cardiac and metabolic dysregulation, the mechanistic pathway(s) of interorgan crosstalk still remain undefined. This study reveals that cardiac-restricted expression of an amino-terminal peptide of GRK2 (ßARKnt) preserves systemic and cardiac insulin responsiveness, and protects against adipocyte maladaptive hypertrophy in a diet-induced obesity model. These data suggest a cardiac-driven mechanism to ameliorate maladaptive cardiac remodeling and improve systemic metabolic homeostasis that may lead to new treatment modalities for cardioprotection in obesity and obesity-related metabolic syndromes.

Assessment of the possible ameliorative effect of curcumin nanoformulation on the submandibular salivary gland of alloxan-induced diabetes in a rat model (Light microscopic and ultrastructural study).

Background: Nowadays, attention is directed to herbal treatments in an attempt to lessen the adverse effects of diabetes. Nanoformulation of curcumin (NC) was shown to enhance stability and water solubility compared to native curcumin. Objective: To examine the effect of different NC concentrations on the histopathological structure of the submandibular salivary gland of diabetic rats. Methods: 28 rats were divided equally into 4 groups. Group I: Control group, Group II (diabetic), III (diabetic + nanocurcumin low dose), and IV (diabetic + nanocurcumin high dose): Rats of groups II, III and IV were injected with a single dose of alloxan (140 mg/kg) to induce diabetes. After 7 days, groups III and IV were treated for 6 weeks with NC (100 mg/kg/day) for group III, and (200 mg/kg/day) for group IV. Submandibular salivary glands were assessed histologically, immunohistochemically using α smooth muscle actin (α SMA) and ultrastructurally. Results: Diabetic samples showed destruction of parenchymal elements of the gland, with thick fiber bundles encircling the excretory ducts and minimal reaction for α SMA. Amelioration of the gland's architecture was detected in groups III and IV with reduction of collagen deposition and elevation of positive immunoreactivity to α SMA. Conclusion: NC profoundly repaired the induced diabetic histopathological and ultrastructural alterations of the gland in a dose dependent manner.

Sex and limb comparisons of neuromuscular function in the morning versus the evening.

The time-of-day influence on neuromuscular function is well-documented, but important details remain elusive. It is currently unknown whether males and females differ in their diurnal variation for optimal neuromuscular performance. The purpose of this study is to identify the time-of-day influence on neuromuscular function between sexes and determine whether these responses differ for the upper versus lower limbs. A group of males (n = 12) and females (n = 15) completed neuromuscular performance testing in the morning (07:00-09:00) and evening (17:00-19:00) on separate days in a randomized order. Maximal force, the normalized rate of force development, EMG, normalized EMG rise, and submaximal force steadiness were compared between morning and evening hours. The main findings show that maximal force was greater in the evening for the knee extensors (d = 0.570, p < 0.01) but not the elbow flexors (d = 0.212, p = 0.281), whereas maximal muscle excitation was greater in the evening for the biceps brachii (d = 0.348, p < 0.01) but not the vastus lateralis (d = 0.075, p = 0.526) with no influence of sex. However, force steadiness during knee extension was superior in the evening versus the morning for males (d = 0.734, p = 0.025) and compared to evening values for females (g = 1.19, p = 0.032). Overall, these findings show that time-of-day affects the knee extensors more than the elbow flexors and that diurnal variability between sexes appears to be task-dependent.

Inter-Day Reliability of Resting Metabolic Rate and Maximal Fat Oxidation during Exercise in Healthy Men Using the Ergostik Gas Analyzer.

The attainment of high inter-day reliability is crucial to determine changes in resting metabolic rate (RMR), respiratory exchange ratio (RER), maximal fat oxidation during exercise (MFO) and the intensity that elicits MFO (Fatmax) after an intervention. This study aimed to analyze the inter-day reliability of RMR, RER, MFO and Fatmax in healthy adults using the Ergostik gas analyzer. Fourteen healthy men (age: 24.4 ± 5.0 years, maximum oxygen uptake (VO2max): 47.5 ± 11.9 mL/kg/min) participated in a repeated-measures study. The study consisted of two identical experimental trials (Day 1 and Day 2) in which the participants underwent an indirect calorimetry assessment at resting and during an incremental exercise test. Stoichiometric equations were used to calculate energy expenditure and substrate oxidation rates. There were no significant differences when comparing RMR (1999.3 ± 273.9 vs. 1955.7 ± 362.6 kcal/day, p = 0.389), RER (0.87 ± 0.05 vs. 0.89 ± 0.05, p = 0.143), MFO (0.32 ± 0.20 vs. 0.31 ± 0.20 g/min, p = 0.776) and Fatmax (45.0 ± 8.6 vs. 46.4 ± 8.4% VO2max, p = 0.435) values in Day 1 vs. Day 2. The inter-day coefficient of variation for RMR, RER, MFO and Fatmax were 4.85 ± 5.48%, 3.22 ± 3.14%, 7.78 ± 5.51%, and 6.51 ± 8.04%, respectively. In summary, the current results show a good inter-day reliability when RMR, RER, MFO and Fatmax are determined in healthy men using the Ergostik gas analyzer.

µ-Crystallin in Mouse Skeletal Muscle Promotes a Shift from Glycolytic toward Oxidative Metabolism.

µ-Crystallin, encoded by the CRYM gene, binds the thyroid hormones, T3 and T4. Because T3 and T4 are potent regulators of metabolism and gene expression, and CRYM levels in human skeletal muscle can vary widely, we investigated the effects of overexpression of Crym. We generated transgenic mice, Crym tg, that expressed Crym protein specifically in skeletal muscle at levels 2.6-147.5 fold higher than in controls. Muscular functions, Ca2+ transients, contractile force, fatigue, running on treadmills or wheels, were not significantly altered, although T3 levels in tibialis anterior (TA) muscle were elevated ~190-fold and serum T4 was decreased 1.2-fold. Serum T3 and thyroid stimulating hormone (TSH) levels were unaffected. Crym transgenic mice studied in metabolic chambers showed a significant decrease in the respiratory exchange ratio (RER) corresponding to a 13.7% increase in fat utilization as an energy source compared to controls. Female but not male Crym tg mice gained weight more rapidly than controls when fed high fat or high simple carbohydrate diets. Although labeling for myosin heavy chains showed no fiber type differences in TA or soleus muscles, application of machine learning algorithms revealed small but significant morphological differences between Crym tg and control soleus fibers. RNA-seq and gene ontology enrichment analysis showed a significant shift towards genes associated with slower muscle function and its metabolic correlate, ß-oxidation. Protein expression showed a similar shift, though with little overlap. Our study shows that µ-crystallin plays an important role in determining substrate utilization in mammalian muscle and that high levels of µ-crystallin are associated with a shift toward greater fat metabolism.

Vo2peak in Adult Survivors of Hodgkin Lymphoma: Rate of Decline, Sex Differences, and Cardiovascular Events.

BACKGROUND: Adult survivors of Hodgkin lymphoma (HL) are at increased risk of cardiovascular (CV) events secondary to mediastinal radiation therapy (RT). OBJECTIVES: In this group of patients, we assessed the association between cardiopulmonary exercise testing (CPET), as determined by percent-predicted peak Vo2 (ppVo2peak), and clinical outcomes, as well as the rate of ppVo2peak decline and sex differences. METHODS: All survivors of HL who were >10 years post chest RT and who underwent ≥1 CPET were enrolled from a single center. Traditional CV and treatment risk factors, along with CV events, were ascertained. RESULTS: A total of 64 patients (67% female; median age 51 years [range 26 to 70 years]) with a median follow-up time after RT of 23 years (range 11 to 41 years), and 141 CPET studies, were included. Median initial ppVo2peak was 91% (range 58% to 138%). ppVo2peak in survivors declined by 7.5 percentage points every 10-year period after RT, as compared with age- and sex-based norms (P = 0.001), even after adjusting for hypertension and history of anthracycline. Both male and female patients had a similar rate of ppVo2peak decline. However, women had a lower ppVo2peak at all times, and they developed abnormal ppVo2peak (≤85%) on average earlier than men (24.1 years vs 47.0 years after RT). Patients with abnormal ppVo2peak vs normal ppVo2peak (>85%), had an increased risk of CV events (59% vs 16%). Abnormal ppVo2peak was independently associated with the risk of CV events (adjusted HR: 6.37; 95% CI: 2.06-19.80; P = 0.001). CONCLUSIONS: Percent-predicted Vo2peak in long-term survivors of HL who were treated with chest RT progressively declined as compared with population- and sex-based norms. Importantly, women developed abnormal ppVo2peak more than 2 decades earlier than male survivors. Abnormal ppVo2peak was associated with an increased risk of CV events in this group of patients.

Comparing Idiopathic Chronic Fatigue and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in Males: Response to Two-Day Cardiopulmonary Exercise Testing Protocol.

(1) Introduction: Multiple studies have shown that peak oxygen consumption is reduced in the majority of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS )patients, using the gold standard for measuring exercise intolerance: cardiopulmonary exercise testing (CPET). A 2-day CPET protocol has shown different results on day 2 in ME/CFS patients compared to sedentary controls. No comparison is known between ME/CFS and idiopathic chronic fatigue (ICF) for 2-day CPET protocols. We compared ME/CFS patients with patients with chronic fatigue who did not fulfill the ME/CFS criteria in a male population and hypothesized a different pattern of response would be present during the 2nd day CPET. (2) Methods: We compared 25 male patients with ICF who had completed a 2-day CPET protocol to an age-/gender-matched group of 26 male ME/CFS patients. Measures of oxygen consumption (VO2), heart rate (HR), systolic and diastolic blood pressure, workload (Work), and respiratory exchange ratio (RER) were collected at maximal (peak) and ventilatory threshold (VT) intensities. (3) Results: Baseline characteristics for both groups were similar for age, body mass index (BMI), body surface area, (BSA), and disease duration. A significant difference was present in the number of patients with fibromyalgia (seven ME/CFS patients vs. zero ICF patients). Heart rate at rest and the RER did not differ significantly between CPET 1 and CPET 2. All other CPET parameters at the ventilatory threshold and maximum exercise differed significantly (p-value between 0.002 and <0.0001). ME/CFS patients showed a deterioration of performance on CPET2 as reflected by VO2 and workload at peak exercise and ventilatory threshold, whereas ICF patients showed improved performance on CPET2 with no significant change in peak workload. (4) Conclusion: This study confirms that male ME/CFS patients have a reduction in exercise capacity in response to a second-day CPET. These results are similar to published results in male ME/CFS populations. Patients diagnosed with ICF show a different response on day 2, more similar to sedentary and healthy controls.