Morin improves dexamethasone-induced muscle atrophy by modulating atrophy-related genes and oxidative stress in female mice.

This study investigated the effect of morin, a flavonoid, on dexamethasone-induced muscle atrophy in C57BL/6J female mice. Dexamethasone (10 mg/kg body weight) for 10 days significantly reduced body weight, gastrocnemius and tibialis anterior muscle mass, and muscle protein in mice. Dexamethasone significantly upregulated muscle atrophy-associated ubiquitin ligases, including atrogin-1 and MuRF-1, and the upstream transcription factors FoxO3a and Klf15.

Oral intake of rice overexpressing ubiquitin ligase inhibitory pentapeptide prevents atrophy in denervated skeletal muscle.

We previously reported that intramuscular injections of ubiquitin ligase CBLB inhibitory pentapeptide (Cblin; Asp-Gly-pTyr-Met-Pro) restored lost muscle mass caused by sciatic denervation. Here, we detected Cblin on the basolateral side of Caco-2 cells after being placed on the apical side, and found that cytochalasin D, a tight junction opener, enhanced Cblin transport. Orally administered Cblin was found in rat plasma, indicating that intact Cblin was absorbed in vitro and in vivo.

MuRF1 deficiency prevents age-related fat weight gain, possibly through accumulation of PDK4 in skeletal muscle mitochondria in older mice.

Recent studies show that muscle mass and metabolic function are interlinked. Muscle RING finger 1 (MuRF1) is a critical muscle-specific ubiquitin ligase associated with muscle atrophy. Yet, the molecular target of MuRF1 in atrophy and aging remains unclear.

Functional rice with tandemly repeated Cbl-b ubiquitin ligase inhibitory pentapeptide prevents denervation-induced muscle atrophy in vivo.

Ubiquitin ligase Casitas B-lineage lymphoma-b (Cbl-b) play a critical role in nonloading-mediated skeletal muscle atrophy: Cbl-b ubiquitinates insulin receptor substrate-1 (IRS-1), leading to its degradation and a resulting loss in muscle mass. We reported that intramuscular injection of a pentapeptide, DGpYMP, which acts as a mimic of the phosphorylation site in IRS-1, significantly inhibited denervation-induced skeletal muscle loss. In order to explore the possibility of the prevention of muscle atrophy by diet therapy, we examined the effects of oral administration of transgenic rice containing Cblin (Cbl-b inhibitor) peptide (DGYMP) on denervation-induced muscle mass loss in frogs.

Morin attenuates dexamethasone-mediated oxidative stress and atrophy in mouse C2C12 skeletal myotubes.

Glucocorticoids are the drugs most commonly used to manage inflammatory diseases. However, they are prone to inducing muscle atrophy by increasing muscle proteolysis and decreasing protein synthesis. Various studies have demonstrated that antioxidants can mitigate glucocorticoid-induced skeletal muscle atrophy.

Ketogenic diet induces skeletal muscle atrophy via reducing muscle protein synthesis and possibly activating proteolysis in mice.

Ketogenic diets (KD) that are very high in fat and low in carbohydrates are thought to simulate the metabolic effects of starvation. We fed mice with a KD for seven days to assess the underlying mechanisms of muscle wasting induced by chronic starvation. This diet decreased the weight of the gastrocnemius (Ga), tibialis anterior (TA) and soleus (Sol) muscles by 23%, 11% and 16%, respectively.

Lactobacillus curvatus CP2998 Prevents Dexamethasone-Induced Muscle Atrophy in C2C12 Myotubes.

To investigate whether heat-killed Lactobacillus curvatus CP2998 (CP2998) inhibits glucocorticoid-induced myotube atrophy which is associated with the ubiquitin-proteasome system, mouse skeletal muscle C2C12 myotubes were treated with dexamethasone (DEX) in the presence or absence of CP2998. DEX exposure significantly decreased myotube diameters and increased mRNA expression levels of MuRF1 and MAFbx, E3 ubiquitin ligases. CP2998 treatment restored myotube diameters and dose dependently decreased mRNA expression levels of these E3 ubiquitin ligases.

Deletion of Prevents Diet-Induced Ectopic Fat Accumulation by Controlling Oxidative Capacity in the Skeletal Muscle.

Brain and muscle arnt-like protein 1 (BMAL1), is a transcription factor known to regulate circadian rhythm. BMAL1 was originally characterized by its high expression in the skeletal muscle. Since the skeletal muscle is the dominant organ system in energy metabolism, the possible functions of BMAL1 in the skeletal muscle include the control of metabolism.

Timing of food intake is more potent than habitual voluntary exercise to prevent diet-induced obesity in mice.

Inappropriate eating habits such as skipping breakfast and eating late at night are associated with risk for abnormal weight-gain and adiposity. We previously reported that time-imposed feeding during the daytime (inactive phase) induces obesity and metabolic disorders accompanied by physical inactivity in mice. The present study compares metabolic changes induced in mice by time-imposed feeding under voluntary wheel-running (RW) and sedentary (SED) conditions to determine the effects of voluntary wheel-running activity on obesity induced in mice by feeding at inappropriate times.

Reactive oxygen species upregulate expression of muscle atrophy-associated ubiquitin ligase Cbl-b in rat L6 skeletal muscle cells.

Unloading-mediated muscle atrophy is associated with increased reactive oxygen species (ROS) production. We previously demonstrated that elevated ubiquitin ligase casitas B-lineage lymphoma-b (Cbl-b) resulted in the loss of muscle volume (Nakao R, Hirasaka K, Goto J, Ishidoh K, Yamada C, Ohno A, Okumura Y, Nonaka I, Yasutomo K, Baldwin KM, Kominami E, Higashibata A, Nagano K, Tanaka K, Yasui N, Mills EM, Takeda S, Nikawa T. Mol Cell Biol 29: 4798-4811, 2009).

Ketogenic diet induces expression of the muscle circadian gene Slc25a25 via neural pathway that might be involved in muscle thermogenesis.

We recently found that the mRNA expression of Slc25a25, a Ca-sensitive ATP carrier in the inner mitochondrial membrane, fluctuates in a circadian manner in mouse skeletal muscle. We showed here that the circadian expression of muscle Slc25a25 was damped in Clock mutant, muscle-specific Bmal1-deficient, and global Bmal1-deficient mice. Furthermore, a ketogenic diet (KD) that induces time-of-day-dependent hypothermia (torpor), induced Slc25a25 mRNA expression in skeletal muscle.

Determination of reference genes that are independent of feeding rhythms for circadian studies of mouse metabolic tissues.

Real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis is a popular method for the measurement of mRNA expression level and is a critical tool for basic research. The identification of suitable reference genes that are stable and not affected by experimental conditions is a critical step in the accurate normalization of RT-PCR. On the other hand, the levels of numerous transcripts exhibit circadian oscillation in various peripheral tissues and it is thought to be regulated by feeding rhythms in addition to the molecular circadian clock.

Short-term feeding at the wrong time is sufficient to desynchronize peripheral clocks and induce obesity with hyperphagia, physical inactivity and metabolic disorders in mice.

Background: The circadian clock regulates various physiological and behavioral rhythms such as feeding and locomotor activity. Feeding at unusual times of the day (inactive phase) is thought to be associated with obesity and metabolic disorders in experimental animals and in humans.

Objective: The present study aimed to determine the underlying mechanisms through which time-of-day-dependent feeding influences metabolic homeostasis.

Structural analysis of the TKB domain of ubiquitin ligase Cbl-b complexed with its small inhibitory peptide, Cblin.

Cbl-b is a RING-type ubiquitin ligase. Previously, we showed that Cbl-b-mediated ubiquitination and proteosomal degradation of IRS-1 contribute to muscle atrophy caused by unloading stress. The phospho-pentapeptide DGpYMP (Cblin) mimics Tyr612-phosphorylated IRS-1 and inhibits the Cbl-b-mediated ubiquitination and degradation of IRS-1 in vitro and in vivo.

Atypical expression of circadian clock genes in denervated mouse skeletal muscle.

The central circadian clock in the suprachiasmatic nucleus of the hypothalamus synchronizes peripheral clocks through neural and humoral signals in most mammalian tissues. Here, we analyzed the effects of unilateral sciatic denervation on the expression of circadian clock- and clock-controlled genes in the gastrocnemius muscles of mice twice per day on days 0, 3, 7, 9, 11 and 14 after denervation and six times on each of days 7 and 28 after denervation to assess the regulation mechanism of the circadian clock in skeletal muscle. Sciatic denervation did not affect systemic circadian rhythms since core body temperature (Day 7), corticosterone secretion (Days 7 and 28), and hepatic clock gene expression remained intact (Days 7 and 28).

N-myristoylated ubiquitin ligase Cbl-b inhibitor prevents on glucocorticoid-induced atrophy in mouse skeletal muscle.

A DGpYMP peptide mimetic of tyrosine(608)-phosphorylated insulin receptor substrate-1 (IRS-1), named Cblin, was previously shown to significantly inhibit Cbl-b-mediated IRS-1 ubiquitination. In the present study, we developed N-myristoylated Cblin and investigated whether it was effective in preventing glucocorticoid-induced muscle atrophy. Using HEK293 cells overexpressing Cbl-b, IRS-1 and ubiquitin, we showed that the 50% inhibitory concentrations of Cbl-b-mediated IRS-1 ubiquitination by N-myristoylated Cblin and Cblin were 30 and 120 μM, respectively.

Free access to a running-wheel advances the phase of behavioral and physiological circadian rhythms and peripheral molecular clocks in mice.

Behavioral and physiological circadian rhythms are controlled by endogenous oscillators in animals. Voluntary wheel-running in rodents is thought to be an appropriate model of aerobic exercise in humans. We evaluated the effects of chronic voluntary exercise on the circadian system by analyzing temporal profiles of feeding, core body temperature, plasma hormone concentrations and peripheral expression of clock and clock-controlled genes in mice housed under sedentary (SED) conditions or given free access to a running-wheel (RW) for four weeks.

Molecular clock regulates daily α1-2-fucosylation of the neural cell adhesion molecule (NCAM) within mouse secondary olfactory neurons.

The circadian clock regulates various behavioral and physiological rhythms in mammals. Circadian changes in olfactory functions such as neuronal firing in the olfactory bulb (OB) and olfactory sensitivity have recently been identified, although the underlying molecular mechanisms remain unknown. We analyzed the temporal profiles of glycan structures in the mouse OB using a high-density microarray that includes 96 lectins, because glycoconjugates play important roles in the nervous system such as neurite outgrowth and synaptogenesis.

Impact of denervation-induced muscle atrophy on housekeeping gene expression in mice.

Introduction: Immobilization induced by experimental denervation leads to rapid and progressive alterations in structural and biochemical properties of skeletal muscle. Real-time reverse transcription-polymerase chain reaction (RT-PCR) is a popular method of elucidating the molecular mechanisms involved in muscle atrophy. Identification of suitable reference genes that are not affected by experimental conditions is a critical step in accurate normalization of real-time RT-PCR.

Dosing schedule-dependent attenuation of dexamethasone-induced muscle atrophy in mice.

Many inflammatory and autoimmune diseases are treated using synthetic glucocorticoids. However, excessive glucocorticoid can often cause unpredictable effects including muscle atrophy. Endogenous glucocorticoid levels robustly fluctuate in a circadian manner and peak just before the onset of the active phase in both humans and nocturnal rodents.

Rantes secreted from macrophages disturbs skeletal muscle regeneration after cardiotoxin injection in Cbl-b-deficient mice.

Deficiency of the Cbl-b ubiquitin ligase gene activates macrophages in mice. This study aimed to elucidate the pathophysiological roles of macrophages in muscle degeneration/regeneration in Cbl-b-deficient mice. We examined immune cell infiltration and cytokine expression in cardiotoxin-injected tibialis anterior muscle of Cbl-b-deficient mice.

Quercetin prevents unloading-derived disused muscle atrophy by attenuating the induction of ubiquitin ligases in tail-suspension mice.

The effects of quercetin (1) were investigated on disused muscle atrophy using mice that underwent tail suspension. Periodic injection of 1 into the gastrocnemius muscle suppressed muscle weight loss and ubiquitin ligase expression. Compound 1 reduced the enhancement of lipid peroxidation in the muscle.