Impairment of Glucose Uptake Induced by Elevated Intracellular Ca in Hippocampal Neurons of Malignant Hyperthermia-Susceptible Mice.

Malignant hyperthermia (MH) is a genetic disorder triggered by depolarizing muscle relaxants or halogenated inhalational anesthetics in genetically predisposed individuals who have a chronic elevated intracellular Ca concentration ([Ca]) in their muscle cells. We have reported that the muscle dysregulation of [Ca] impairs glucose uptake, leading to the development of insulin resistance in two rodent experimental models. In this study, we simultaneously measured the [Ca] and glucose uptake in single enzymatically isolated hippocampal pyramidal neurons from wild-type (WT) and MH-R163C mice.

Harnessing Passive Pulsatile Shear Stress for Alzheimer's Disease Prevention and Intervention.

 Alzheimer's disease (AD) affects more than 40 million people worldwide and is the leading cause of dementia. This disease is a challenge for both patients and caregivers and puts a significant strain on the global healthcare system. To address this issue, the Lancet Commission recommends focusing on reducing modifiable lifestyle risk factors such as hypertension, diabetes, and physical inactivity.

Post-Anesthesia Cognitive Dysfunction in Mice Is Associated with an Age-Related Increase in Neuronal Intracellular [Ca]-Neuroprotective Effect of Reducing Intracellular [Ca]: In Vivo and In Vitro Studies.

Postoperative cognitive dysfunction (POCD) is a common disorder after general anesthesia in elderly patients, the precise mechanisms of which remain unclear. We investigated the effect of isoflurane with or without dantrolene pretreatment on intracellular calcium concentration ([Ca]), reactive oxygen species (ROS) production, cellular lactate dehydrogenase (LDH) leak, calpain activity, and cognitive function using the Morris water maze test of young (3 months), middle-aged (12-13 months), and aged (24-25 months) C57BL6/J mice. Aged cortical and hippocampal neurons showed chronically elevated [Ca] compared to young neurons.

Enhancing Muscle Intracellular Ca Homeostasis and Glucose Uptake: Passive Pulsatile Shear Stress Treatment in Type 2 Diabetes.

Type 2 diabetes mellitus (T2D) is a significant global public health problem that has seen a substantial increase in the number of affected individuals in recent decades. In a murine model of T2D (db/db), we found several abnormalities, including aberrant intracellular calcium concentration ([Ca]), decreased glucose transport, increased production of reactive oxygen species (ROS), elevated levels of pro-inflammatory interleukins and creatine phosphokinase (CK), and muscle weakness. Previously, we demonstrated that passive pulsatile shear stress, generated by sinusoidal (headward-forward) motion, using a motion platform that provides periodic acceleration of the whole body in the Z plane (pGz), induces the synthesis of nitric oxide (NO) mediated by constitutive nitric oxide synthase (eNOS and nNOS).

A Nonrandomized Trial of the Effects of Passive Simulated Jogging on Short-Term Heart Rate Variability in Type 2 Diabetic Subjects.

Background: Diabetes mellitus has reached global epidemic proportions, with type 2 diabetes (T2DM) comprising more than 90% of all subjects with diabetes. Cardiovascular autonomic neuropathy (CAN) frequently occurs in T2DM. Heart rate variability (HRV) reflects a neural balance between the sympathetic and parasympathetic autonomic nervous systems (ANS) and a marker of CAN.

Smooth Muscle Cells of Dystrophic (mdx) Mice Are More Susceptible to Hypoxia; The Protective Effect of Reducing Ca Influx.

Duchenne muscular dystrophy (DMD) is an inherited muscular disorder caused by mutations in the dystrophin gene. DMD patients have hypoxemic events due to sleep-disordered breathing. We reported an anomalous regulation of resting intracellular Ca ([Ca]) in vascular smooth muscle cells (VSMCs) from a mouse (mdx) model of DMD.

Non-Invasive Pulsatile Shear Stress Modifies Endothelial Activation; A Narrative Review.

The monolayer of cells that line both the heart and the entire vasculature is the endothelial cell (EC). These cells respond to external and internal signals, producing a wide array of primary or secondary messengers involved in coagulation, vascular tone, inflammation, and cell-to-cell signaling. Endothelial cell activation is the process by which EC changes from a quiescent cell phenotype, which maintains cellular integrity, antithrombotic, and anti-inflammatory properties, to a phenotype that is prothrombotic, pro-inflammatory, and permeable, in addition to repair and leukocyte trafficking at the site of injury or infection.

The effects of a motorized passive simulated jogging device on descent of the arterial pulse waveform dicrotic notch: A single arm placebo-controlled cross-over trial.

Whole Body Periodic Acceleration (WBPA, pGz), is a bed that moves the body headward to forward, adds pulses to the circulation inducing descent of the dicrotic notch (DN) on the pulse waveform with an increase in a/b ratio (a = the height of the pulse waveform and b = the height of the secondary wave). Since the WBPA is large, heavy, and non-portable, we engineered a portable device (Jogging Device, JD). JD simulates passive jogging and introduces pulsations to the circulation.

The Role of the Na/Ca Exchanger in Aberrant Intracellular Ca in Cardiomyocytes of Chagas-Infected Rodents.

Chagas disease is produced by the parasite , which is the leading cause of death and morbidity in Latin America. We have shown that in patients with Chagas cardiomyopathy, there is a chronic elevation of diastolic Ca concentration ([Ca]), associated with deterioration to further address this issue, we explored the role Na/Ca exchanger (NCX). Experiments were carried out in noninfected C57BL/6 mice and infected with blood-derived trypomastigotes of the Y strain.

Chronic Elevation of Skeletal Muscle [Ca] Impairs Glucose Uptake. An and Study.

Skeletal muscle is the primary site of insulin-mediated glucose uptake through the body and, therefore, an essential contributor to glucose homeostasis maintenance. We have recently provided evidence that chronic elevated intracellular Ca concentration at rest [(Ca)] compromises glucose homeostasis in malignant hyperthermia muscle cells. To further investigate how chronic elevated muscle [Ca] modifies insulin-mediated glucose homeostasis, we measured [Ca] and glucose uptake and in intact polarized muscle cells from glucose-intolerant -p.

The Effects of Passive Simulated Jogging on Parameters of Explosive Handgrip in Nondiabetics and Type 2 Diabetics: A Single Arm Study.

Aims: Type 2 diabetes (T2D) is associated with sarcopenia and decreased muscle strength. Explosive and isometric voluntary handgrip strengths (EHGS and HGS) are frequently utilized methods to ascertain health status and a marker of overall muscle strength. We have previously shown that a portable, motorized device, which produces effortless, rapid stepping in place (passive simulated jogging device (JD)), improves glucose homeostasis.

A novel RyR1-selective inhibitor prevents and rescues sudden death in mouse models of malignant hyperthermia and heat stroke.

Mutations in the type 1 ryanodine receptor (RyR1), a Ca release channel in skeletal muscle, hyperactivate the channel to cause malignant hyperthermia (MH) and are implicated in severe heat stroke. Dantrolene, the only approved drug for MH, has the disadvantages of having very poor water solubility and long plasma half-life. We show here that an oxolinic acid-derivative RyR1-selective inhibitor, 6,7-(methylenedioxy)-1-octyl-4-quinolone-3-carboxylic acid (Compound 1, Cpd1), effectively prevents and treats MH and heat stroke in several mouse models relevant to MH.

Cardioprotective Effect of Whole Body Periodic Acceleration in Dystrophic Phenotype Rodent.

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting and the development of a dilated cardiomyopathy (DCM), which is the leading cause of death in DMD patients. Despite knowing the cause of DMD, there are currently no therapies which can prevent or reverse its inevitable progression. We have used whole body periodic acceleration (WBPA) as a novel tool to enhance intracellular constitutive nitric oxide (NO) production.

Whole body periodic acceleration (pGz) improves endotoxin induced cardiomyocyte contractile dysfunction and attenuates the inflammatory response in mice.

Sepsis-induces myocardial contractile dysfunction. We previously showed that whole body periodic acceleration (pGz), the sinusoidal motion of the supine body head-foot ward direction significantly improves survival and decreases microvascular permeability in a lethal model of sepsis. We tested the hypothesis that pGz improves LPS induced cardiomyocyte contractile dysfunction and decreases LPS pro-inflammatory cytokine response when applied pre- or post-treatment.

A single arm trial using passive simulated jogging for blunting acute hyperglycemia.

Glycemic fluctuations increase oxidative stress, promote endothelial dysfunction and cardiovascular disease. Reducing glycemic fluctuations is beneficial. We previously reported that a portable motorized passive simulated jogging device, (JD) reduces 24 h glycemic indices in type 2 and non-diabetic subjects.

The Endothelium as a Therapeutic Target in Diabetes: A Narrative Review and Perspective.

Diabetes has reached worldwide epidemic proportions, and threatens to be a significant economic burden to both patients and healthcare systems, and an important driver of cardiovascular mortality and morbidity. Improvement in lifestyle interventions (which includes increase in physical activity via exercise) can reduce diabetes and cardiovascular disease mortality and morbidity. Encouraging a population to increase physical activity and exercise is not a simple feat particularly in individuals with co-morbidities (obesity, heart disease, stroke, peripheral vascular disease, and those with cognitive and physical limitations).

Molecular Modification of Transient Receptor Potential Canonical 6 Channels Modulates Calcium Dyshomeostasis in a Mouse Model Relevant to Malignant Hyperthermia.

Background: Pharmacologic modulation has previously shown that transient receptor potential canonical (TRPC) channels play an important role in the pathogenesis of malignant hyperthermia. This study tested the hypothesis that genetically suppressing the function of TRPC6 can partially ameliorate muscle cation dyshomeostasis and the response to halothane in a mouse model relevant to malignant hyperthermia.

Methods: This study examined the effect of overexpressing a muscle-specific nonconducting dominant-negative TRPC6 channel in 20 RYR1-p.

Endothelial pulsatile shear stress is a backstop for COVID-19.

There has not been any means to inhibit replication of the SARS-CoV-2 virus responsible for the rapid, deadly spread of the COVID-19 pandemic and an effective, safe, tested across diverse populations vaccine still requires extensive investigation. This review deals with the repurpose of a wellness technology initially fabricated for combating physical inactivity by increasing muscular activity. Its action increases pulsatile shear stress (PSS) to the endothelium such that the bioavailability of nitric oxide (NO) and other mediators are increased throughout the body.

Can Physical Activity While Sedentary Produce Health Benefits? A Single-Arm Randomized Trial.

Background: Sedentary time poses a risk to health. Substituting physical activity for inactivity is obvious but this requires a behavior change. Interventions advocated to decrease uninterrupted physical inactivity (defined as Metabolic Equivalent of Task (METS) less than 1.

Memory and Learning Deficits Are Associated With Ca Dyshomeostasis in Normal Aging.

Neuronal intracellular Ca homeostasis is critical to the normal physiological functions of neurons and neuronal Ca dyshomeostasis has been associated with the age-related decline of cognitive functions. Accumulated evidence indicates that the underlying mechanism for this is that abnormal intracellular Ca levels stimulate the dysregulation of intracellular signaling, which subsequently induces neuronal cell death. We examined intracellular Ca homeostasis in cortical ( and hippocampal ( neurons from young (3-months), middle-age (12-months), and aged (24-months) wild type C57BL6J mice.

Transient Receptor Potential Cation Channels and Calcium Dyshomeostasis in a Mouse Model Relevant to Malignant Hyperthermia.

Background: Until recently, the mechanism for the malignant hyperthermia crisis has been attributed solely to sustained massive Ca release from the sarcoplasmic reticulum on exposure to triggering agents. This study tested the hypothesis that transient receptor potential cation (TRPC) channels are important contributors to the Ca dyshomeostasis in a mouse model relevant to malignant hyperthermia.

Methods: This study examined the mechanisms responsible for Ca dyshomeostasis in RYR1-p.

Increases in [IP3]i aggravates diastolic [Ca2+] and contractile dysfunction in Chagas' human cardiomyocytes.

Chagas cardiomyopathy is the most severe manifestation of human Chagas disease and represents the major cause of morbidity and mortality in Latin America. We previously demonstrated diastolic Ca2+ alterations in cardiomyocytes isolated from Chagas' patients to different degrees of cardiac dysfunction. In addition, we have found a significant elevation of diastolic [Na+]d in Chagas' cardiomyocytes (FCII>FCI) that was greater than control.

Portable Gentle Jogger Improves Glycemic Indices in Type 2 Diabetic and Healthy Subjects Living at Home: A Pilot Study.

Background: Physical inactivity is a high-risk factor for type 2 diabetes. Increased physical activity improves indices of glycemic control. Continuous glucose monitoring (CGM) allows the investigation of glycemic control during activities of daily living.