Hydrogen Sulfide Deficiency and Therapeutic Targeting in Cardiometabolic HFpEF: Evidence for Synergistic Benefit With GLP-1/Glucagon Agonism.

Heart failure with preserved ejection fraction (HFpEF) presents significant treatment challenges. We assessed hydrogen sulfide (HS) bioavailability in HFpEF patients and 2 animal models: the "2-hit" L-NAME + high-fat diet mouse model and ZSF1 obese rats. HS levels were significantly reduced in patients and both models, linked to decreased cystathionine-γ-lyase expression and increased sulfide quinone oxidoreductase.

Effect of training status on muscle excitation and neuromuscular fatigue with resistance exercise with and without blood flow restriction in young men.

This study compared muscle (vastus lateralis) excitation, muscle activation, and neuromuscular fatigue in response to low-load resistance exercise with blood flow restriction (LLBFR), medium-load resistance exercise with blood flow restriction (MLBFR), and high-load resistance exercise (HLRE) in resistance-trained (RT; n = 15) and untrained (UT; n = 14) college-aged males. Muscle excitation and activation were measured using surface electromyography (sEMG) and defined as the maximal root mean square amplitudes (RMS AMP) and the integrated area under the sEMG curve (iEMG) per repetition. Neuromuscular fatigue was defined as the reduction in peak torque measured during the postexercise knee extensor maximal isometric contractions (MVIC) relative to the pre-exercise MVIC.

Exercise Therapy Rescues Skeletal Muscle Dysfunction and Exercise Intolerance in Cardiometabolic HFpEF.

Exercise intolerance, a hallmark of heart failure with preserved ejection fraction (HFpEF) exacerbated by obesity, involves unclear mechanisms related to skeletal muscle metabolism. In a "2-hit" model of HFpEF, we investigated the ability of exercise therapy (voluntary wheel running) to reverse skeletal muscle dysfunction and exercise intolerance. Using state-of-the-art metabolic cages and a multiomic approach, we demonstrate exercise can rescue dysfunctional skeletal muscle lipid and branched-chain amino acid oxidation and restore exercise capacity in mice with cardiometabolic HFpEF.

Dysregulation of Nitrosylation Dynamics Promotes Nitrosative Stress and Contributes to Cardiometabolic Heart Failure with Preserved Ejection Fraction.

Background: Recent reports suggest increased myocardial iNOS expression leads to excessive protein -nitrosylation, contributing to the pathophysiology of HFpEF. However, the relationship between NO bioavailability, dynamic regulation of protein -nitrosylation by trans- and de-nitrosylases, and HFpEF pathophysiology has not been elucidated. Here, we provide novel insights into the delicate interplay between NO bioavailability and protein -nitrosylation in HFpEF.

Nitric oxide donors rescue metabolic and mitochondrial dysfunction in obese Alzheimer's model.

Reduced nitric oxide (NO) bioavailability is a pathological link between obesity and Alzheimer's disease (AD). Obesity-associated metabolic and mitochondrial bioenergetic dysfunction are key drivers of AD pathology. The hypothalamus is a critical brain region during the development of obesity and dysfunction is an area implicated in the development of AD.

Hydrogen Sulfide Deficiency and Therapeutic Targeting in Cardiometabolic HFpEF: Evidence for Synergistic Benefit with GLP-1/Glucagon Agonism.

Background: Heart failure with preserved ejection fraction (HFpEF) is a significant public health concern with limited treatment options. Dysregulated nitric oxide-mediated signaling has been implicated in HFpEF pathophysiology, however, little is known about the role of endogenous hydrogen sulfide (H S) in HFpEF.

Objectives: This study evaluated H S bioavailability in patients and two animal models of cardiometabolic HFpEF and assessed the impact of H S on HFpEF severity through alterations in endogenous H S production and pharmacological supplementation.

Adjunctive therapy with an oral HS donor provides additional therapeutic benefit beyond SGLT2 inhibition in cardiometabolic heart failure with preserved ejection fraction.

Background And Purpose: Sodium glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a potent therapy for heart failure with preserved ejection fraction (HFpEF). Hydrogen sulphide (HS), a well-studied cardioprotective agent, could be beneficial in HFpEF. SGLT2i monotherapy and combination therapy involving an SGLT2i and HS donor in two preclinical models of cardiometabolic HFpEF was investigated.

Impact of low-load resistance exercise with and without blood flow restriction on muscle strength, endurance, and oxidative capacity: A pilot study.

Low-load resistance exercise (LLRE) to failure can increase muscle mass, strength, endurance, and mitochondrial oxidative capacity (OXPHOS). However, the impact of adding blood flow restriction to low-load resistance exercise (LLBFR) when matched for volume on these outcomes is incompletely understood. This pilot study examined the impact of 6 weeks of single-legged LLBFR and volume-matched LLRE on thigh bone-free lean mass, strength, endurance, and mitochondrial OXPHOS.

Early Renal Denervation Attenuates Cardiac Dysfunction in Heart Failure With Preserved Ejection Fraction.

Background: The renal sympathetic nervous system modulates systemic blood pressure, cardiac performance, and renal function. Pathological increases in renal sympathetic nerve activity contribute to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). We investigated the effects of renal sympathetic denervation performed at early or late stages of HFpEF progression.

The Effect of Watermelon Juice Supplementation on Heart Rate Variability and Metabolic Response during an Oral Glucose Challenge: A Randomized, Double-Blind, Placebo-Controlled Crossover Trial.

Heart rate variability (HRV) provides a simple method to evaluate autonomic function in health and disease. A reduction in HRV may indicate autonomic dysfunction and is strongly associated with aspects of cardiometabolic disease, including hyperglycemia. Reduced nitric oxide (NO) bioavailability is also implicated in the development of cardiometabolic disease and autonomic dysfunction.

Detrimental Changes in Health during Menopause: The Role of Physical Activity.

Midlife women experience changes in cardiometabolic, physical, and psychosocial health during menopause that negatively impacts their overall quality of life. Factors that contribute to these increases in cardiometabolic risk include weight gain as well as increases in fat mass (particularly abdominal adiposity), insulin resistance, and vascular dysfunction. Other deleterious changes in physical health (e.

Glucagon-like peptide-1/glucagon receptor agonism associates with reduced metabolic adaptation and higher fat oxidation: A randomized trial.

Objective: This study tested the hypothesis that treatment with the glucagon-like peptide-1/glucagon receptor agonist SAR425899 would lead to a smaller decrease in sleeping metabolic rate (SMR; kilocalories/day) than expected from the loss of lean and fat mass (metabolic adaptation).

Methods: This Phase 1b, double-blind, randomized, placebo-controlled study was conducted at two centers in inpatient metabolic wards. Thirty-five healthy males and females with overweight and obesity (age = 36.

Loss of Adipocyte STAT5 Confers Increased Depot-Specific Adiposity in Male and Female Mice That Is Not Associated With Altered Adipose Tissue Lipolysis.

STATs (Signal Transducers and Activators of Transcription) 5A and 5B are induced during adipocyte differentiation and are primarily activated by growth hormone (GH) and prolactin in fat cells. Previous studies in mice lacking adipocyte GH receptor or STAT5 support their roles in lipolysis-mediated reduction of adipose tissue mass. Male and female mice harboring adipocyte-specific deletion of both STAT5 genes (STAT5) exhibit increased subcutaneous or inguinal adipose tissue mass, but no changes in visceral or gonadal fat mass.

Effect of watermelon supplementation on exercise performance, muscle oxygenation, and vessel diameter in resistance-trained men.

Introduction: Watermelon shows promise as an ergogenic aid due to its high concentration of L-citrulline, vitamins, minerals, and antioxidants.

Purpose: The purpose of this study was to examine the effect of watermelon supplementation on exercise performance, muscle oxygenation, and vessel diameter.

Methods: In a crossover design fashion, 15 resistance-trained men (22.

Supplemental Watermelon Juice Attenuates Acute Hyperglycemia-Induced Macro-and Microvascular Dysfunction in Healthy Adults.

Background: Acute hyperglycemia reduces NO bioavailability and causes macro- and microvascular dysfunction. Watermelon juice (WMJ) is a natural source of the amino acid citrulline, which is metabolized to form arginine for the NO cycle and may improve vascular function.

Objectives: We examined the effects of 2 weeks of WMJ compared to a calorie-matched placebo (PLA) to attenuate acute hyperglycemia-induced vascular dysfunction.

Reliability of measurements of energy expenditure and substrate oxidation using whole-room indirect calorimetry.

Objective: This analysis aimed to measure the intraparticipant reliability-the intraclass correlation coefficient-of all the components of daily energy expenditure (EE) (24-hour EE, sleep EE, resting EE, basal EE, and thermic effect of food) over a period of 3 consecutive days in 35 study participants.

Methods: The components of daily EE and substrate use (respiratory exchange ratio) were measured over 3 consecutive days before and after a 3-week 1,000-kcal/d caloric restriction/weight-loss intervention.

Results: There was a high degree of reliability for sleep EE (96.

Exercise reduced the formation of new adipocytes in the adipose tissue of mice in vivo.

Exercise has beneficial effects on metabolism and health. Although the skeletal muscle has been a primary focus, exercise also mediates robust adaptations in white adipose tissue. To determine if exercise affects in vivo adipocyte formation, fifty-two, sixteen-week-old C57BL/6J mice were allowed access to unlocked running wheels [Exercise (EX) group; n = 13 males, n = 13 females] or to locked wheels [Sedentary (SED) group; n = 13 males, n = 13 females] for 4-weeks.

An Ethanolic Extract of Artemisia dracunculus L. Enhances the Metabolic Benefits of Exercise in Diet-induced Obese Mice.

Purpose: The purpose of this study was to determine the effect of an ethanolic extract of Artemisia dracunculus L. (5011) combined with exercise on in vivo glucose and fat metabolism in diet-induced obese male mice.

Methods: After 8 wk of high-fat diet (HFD) feeding, 52 mice were randomly allocated to a voluntary wheel running group (HFD Ex), a 5011 + HFD sedentary group (5011 Sed), a 5011 + HFD Ex (5011 Ex), or an HFD sedentary group (HFD Sed) for 4 wk.

Adaptive Fat Oxidation Is Coupled with Increased Lipid Storage in Adipose Tissue of Female Mice Fed High Dietary Fat and Sucrose.

Western diets high in fat and sucrose are associated with metabolic syndrome (MetS). Although the prevalence of MetS in women is comparable to that in men, metabolic adaptations in females to Western diet have not been reported in preclinical studies. This study investigates the effects of Western diet on risk factors for MetS in female mice.

Dynamic Glucose Disposal is Driven by Reduced Endogenous Glucose Production in Response to Voluntary Wheel Running: A Stable Isotope Approach.

To resolve both the systems level and molecular mechanisms responsible for exercise induced improvements in glucose tolerance, we sought to test the effect of voluntary wheel running exercise on postprandial glucose dynamics. We utilized a stable isotope labeled oral glucose tolerance test (SI-OGTT) incorporating complimentary deuterium glucose tracers at 1:1 ratio (2-H-glucose and 6-6 H-glucose; 2g/kg lean body mass) to distinguish between endogenous glucose production (EGP) and whole-body glucose disposal. SI-OGTT was performed in C57BL/6J mice after 8 weeks on a high fat diet (45% fat).

Metabolic flexibility is impaired in response to acute exercise in the young offspring of mothers with type 2 diabetes.

We assessed metabolic flexibility (MF) via a mixed meal in a group of young, healthy participants with a positive family history of maternal type 2 diabetes (T2D) (FH+) and those without a family history of T2D (FH-) under three distinct conditions; baseline (BL; no previous exercise), 1-h post high intensity interval exercise (1H), and 48-h post exercise recovery. On separate visits, participants completed a single bout of high intensity interval exercise (HIIE) and repeated the MMTT 1-h (1H) and 48 h (48H) postexercise. FH+ participants were not able to suppress fat oxidation 1-h post exercise (1H) as effectively as FH- participants were, however, this response was improved when measured at the 48H visit.

l-Citrulline Supplementation: Impact on Cardiometabolic Health.

Diminished bioavailability of nitric oxide (NO), the gaseous signaling molecule involved in the regulation of numerous vital biological functions, contributes to the development and progression of multiple age- and lifestyle-related diseases. While l-arginine is the precursor for the synthesis of NO by endothelial-nitric oxide synthase (eNOS), oral l-arginine supplementation is largely ineffective at increasing NO synthesis and/or bioavailability for a variety of reasons. l-citrulline, found in high concentrations in watermelon, is a neutral alpha-amino acid formed by enzymes in the mitochondria that also serves as a substrate for recycling l-arginine.