The core circadian clock factor, Bmal1, transduces sex-specific differences in both rhythmic and non-rhythmic gene expression in the mouse heart.

It has been well established that cardiovascular diseases exhibit significant differences between sexes in both preclinical models and humans. In addition, there is growing recognition that disrupted circadian rhythms can contribute to the onset and progression of cardiovascular diseases. However, little is known about sex differences between the cardiac circadian clock and circadian transcriptomes in mice.

New role for cardiomyocyte in the regulation of sex-specific heart transcriptomes.

It has been well established that cardiovascular diseases exhibit significant differences between sexes in both preclinical models and humans. In addition, there is growing recognition that disrupted circadian rhythms can contribute to the onset and progression of cardiovascular diseases. However little is known about sex differences between the cardiac circadian clock and circadian transcriptomes in mice.

Circadian Regulation of Cardiac Arrhythmias and Electrophysiology.

Circadian rhythms in physiology and behavior are ≈24-hour biological cycles regulated by internal biological clocks (ie, circadian clocks) that optimize organismal homeostasis in response to predictable environmental changes. These clocks are present in virtually all cells in the body, including cardiomyocytes. Many decades ago, clinicians and researchers became interested in studying daily patterns of triggers for sudden cardiac death, the incidence of sudden cardiac death, and cardiac arrhythmias.

Feeding Behavior Modifies the Circadian Variation in RR and QT intervals by Distinct Mechanisms in Mice.

Rhythmic feeding behavior is critical for regulating the phase and amplitude in the ≍24-hour variation of the heart rate (RR intervals), ventricular repolarization (QT intervals), and core body temperature in mice. We hypothesized the changes in cardiac electrophysiology associated with feeding behavior were secondary to changes in core body temperature. Telemetry was used to record electrocardiograms and core body temperature in mice during ad libitum-fed conditions and after inverting normal feeding behavior by restricting food access to the light cycle.

Defining the age-dependent and tissue-specific circadian transcriptome in male mice.

Cellular circadian clocks direct a daily transcriptional program that supports homeostasis and resilience. Emerging evidence has demonstrated age-associated changes in circadian functions. To define age-dependent changes at the systems level, we profile the circadian transcriptome in the hypothalamus, lung, heart, kidney, skeletal muscle, and adrenal gland in three age groups.

Time Restricted Feeding to the Light Cycle Dissociates Canonical Circadian Clocks and Physiological Rhythms in Heart Rate.

Circadian rhythms are approximate 24-h biological cycles that optimize molecular and physiological functions to predictable daily environmental changes in order to maintain internal and organismal homeostasis. Environmental stimuli (light, feeding, activity) capable of altering the phase of molecular rhythms are important tools employed by circadian biologists to increase understanding of the synchronization of circadian rhythms to the environment and to each other within multicellular systems. The central circadian clock, located in the suprachiasmatic nucleus (SCN) of the hypothalamus is largely responsive to light and is thought to entrain the phase of peripheral clocks via neurohumoral signals.

The role of the cardiomyocyte circadian clocks in ion channel regulation and cardiac electrophysiology.

Daily variations in cardiac electrophysiology and the incidence for different types of arrhythmias reflect ≈24 h changes in the environment, behaviour and internal circadian rhythms. This article focuses on studies that use animal models to separate the impact that circadian rhythms, as well as changes in the environment and behaviour, have on 24 h rhythms in heart rate and ventricular repolarization. Circadian rhythms are initiated at the cellular level by circadian clocks, transcription-translation feedback loops that cycle with a periodicity of 24 h.

Timing of food intake in mice unmasks a role for the cardiomyocyte circadian clock mechanism in limiting QT-interval prolongation.

Cardiac electrophysiological studies demonstrate that restricting the feeding of mice to the light cycle (time restricted feeding or TRF) causes a pronounced change in heart rate and ventricular repolarization as measured by the RR- and QT-interval, respectively. TRF slows heart rate and shifts the peak (acrophase) of the day/night rhythms in the RR- and QT-intervals from the light to the dark cycle. This study tested the hypothesis that these changes in cardiac electrophysiology are driven by the cardiomyocyte circadian clock mechanism.

Magnetic twitch assessment of diaphragm and quadriceps weakness in critically ill mechanically ventilated patients.

Critically ill mechanically ventilated (MV) patients develop significant muscle weakness, which has major clinical consequences. There remains uncertainty, however, regarding the severity of leg weakness, the precise relationship between muscle strength and thickness, and the risk factors for weakness in MV patients. We therefore measured both diaphragm (PdiTw) and quadriceps (QuadTw) strength in MV patients using magnetic stimulation and compared strength to muscle thickness.

A randomized controlled trial to determine whether beta-hydroxy-beta-methylbutyrate and/or eicosapentaenoic acid improves diaphragm and quadriceps strength in critically Ill mechanically ventilated patients.

Background: Intensive care unit acquired weakness is a serious problem, contributing to respiratory failure and reductions in ambulation. Currently, there is no pharmacological therapy for this condition. Studies indicate, however, that both beta-hydroxy-beta-methylbutyrate (HMB) and eicosapentaenoic acid (EPA) increase muscle function in patients with cancer and in older adults.

Cardiomyocyte Deletion of Exacerbates QT- and RR-Interval Prolongation in Mice.

Circadian rhythms are generated by cell autonomous circadian clocks that perform a ubiquitous cellular time-keeping function and cell type-specific functions important for normal physiology. Studies show inducing the deletion of the core circadian clock transcription factor in adult mouse cardiomyocytes disrupts cardiac circadian clock function, cardiac ion channel expression, slows heart rate, and prolongs the QT-interval at slow heart rates. This study determined how inducing the deletion of in adult cardiomyocytes impacted the electrophysiological phenotype of a knock-in mouse model for the arrhythmogenic long QT syndrome ( ).

Mitoquinone mesylate (MitoQ) prevents sepsis-induced diaphragm dysfunction.

Sepsis-induced diaphragm dysfunction is a major contributor to respiratory failure in mechanically ventilated patients. There are no pharmacological treatments for this syndrome, but studies suggest that diaphragm weakness is linked to mitochondrial free radical generation. We hypothesized that administration of mitoquinone mesylate (MitoQ), a mitochondrially targeted free radical scavenger, would prevent sepsis-induced diaphragm dysfunction.

Skeletal muscle-specific calpastatin overexpression mitigates muscle weakness in aging and extends life span.

Calpain activation has been postulated as a potential contributor to the loss of muscle mass and function associated with both aging and disease, but limitations of previous experimental approaches have failed to completely examine this issue. We hypothesized that mice overexpressing calpastatin (CalpOX), an endogenous inhibitor of calpain, solely in skeletal muscle would show an amelioration of the aging muscle phenotype. We assessed four groups of mice (age in months): ) young wild type (WT; 5.

Circadian clocks regulate cardiac arrhythmia susceptibility, repolarization, and ion channels.

Daily changes in the incidence of sudden cardiac death (SCD) reveal an interaction between environmental rhythms and internal circadian rhythms. Circadian rhythms are physiological rhythms that alter physiology to anticipate daily changes in the environment. They reflect coordinated activity of cellular circadian clocks that exist throughout the body.

Exercise mitigates sleep-loss-induced changes in glucose tolerance, mitochondrial function, sarcoplasmic protein synthesis, and diurnal rhythms.

Objective: Sleep loss has emerged as a risk factor for the development of impaired glucose tolerance. The mechanisms underpinning this observation are unknown; however, both mitochondrial dysfunction and circadian misalignment have been proposed. Because exercise improves glucose tolerance and mitochondrial function, and alters circadian rhythms, we investigated whether exercise may counteract the effects induced by inadequate sleep.

Does Standard Physical Therapy Increase Quadriceps Strength in Chronically Ventilated Patients? A Pilot Study.

Objectives: Physical therapy is standard care for mechanically ventilated patients, but there is no evidence, using nonvolitional, objective measurements, that physical therapy increases muscle strength in this population. The present study tested the hypothesis that 2 weeks of standard, conventional physical therapy provided at a ventilator weaning facility would increase quadriceps strength in mechanically ventilated patients.

Design: Prospective observational study.

Long QT Syndrome Type 2: Emerging Strategies for Correcting Class 2 () Mutations and Identifying New Patients.

Significant advances in our understanding of the molecular mechanisms that cause congenital long QT syndrome (LQTS) have been made. A wide variety of experimental approaches, including heterologous expression of mutant ion channel proteins and the use of inducible pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from LQTS patients offer insights into etiology and new therapeutic strategies. This review briefly discusses the major molecular mechanisms underlying LQTS type 2 (LQT2), which is caused by loss-of-function (LOF) mutations in the gene (also known as the human ether-à-go-go-related gene or ).

MitoTEMPOL, a mitochondrial targeted antioxidant, prevents sepsis-induced diaphragm dysfunction.

Clinical studies indicate that sepsis-induced diaphragm dysfunction is a major contributor to respiratory failure in mechanically ventilated patients. Currently there is no drug to treat this form of diaphragm weakness. Sepsis-induced muscle dysfunction is thought to be triggered by excessive mitochondrial free radical generation; we therefore hypothesized that therapies that target mitochondrial free radical production may prevent sepsis-induced diaphragm weakness.

SS31, a mitochondrially targeted antioxidant, prevents sepsis-induced reductions in diaphragm strength and endurance.

Sepsis-induced diaphragm dysfunction contributes to respiratory failure and mortality in critical illness. There are no treatments for this form of diaphragm weakness. Studies show that sepsis-induced muscle dysfunction is triggered by enhanced mitochondrial free radical generation.

Taurine administration ablates sepsis induced diaphragm weakness.

Infection induced diaphragm weakness is a major contributor to death and prolonged mechanical ventilation in critically ill patients. Infection induced muscle dysfunction is associated with activation of muscle proteolytic enzymes, and taurine is known to suppress proteolysis. We therefore postulated that taurine administration may prevent infection induced diaphragm dysfunction.

Mitochondria and Critical Illness.

Classically, mitochondria have largely been believed to influence the development of illness by modulating cell metabolism and determining the rate of production of high-energy phosphate compounds (eg, adenosine triphosphate). It is now recognized that this view is simplistic and that mitochondria play key roles in many other processes, including cell signaling, regulating gene expression, modulating cellular calcium levels, and influencing the activation of cell death pathways (eg, caspase activation). Moreover, these multiple mitochondrial functional characteristics are now known to influence the evolution of cellular and organ function in many disease states, including sepsis, ICU-acquired skeletal muscle dysfunction, acute lung injury, acute renal failure, and critical illness-related immune function dysregulation.

Temperature as a Circadian Marker in Older Human Subjects: Relationship to Metabolic Syndrome and Diabetes.

Background: Circadian rhythms are characterized by approximate 24-hour oscillations in physiological and behavioral processes. Disruptions in these endogenous rhythms, most commonly associated with shift work and/or lifestyle, are recognized to be detrimental to health. Several studies have demonstrated a high correlation between disrupted circadian rhythms and metabolic disease.

Muscle-specific loss of Bmal1 leads to disrupted tissue glucose metabolism and systemic glucose homeostasis.

Background: Diabetes is the seventh leading cause of death in the USA, and disruption of circadian rhythms is gaining recognition as a contributing factor to disease prevalence. This disease is characterized by hyperglycemia and glucose intolerance and symptoms caused by failure to produce and/or respond to insulin. The skeletal muscle is a key insulin-sensitive metabolic tissue, taking up ~80 % of postprandial glucose.