Atrophy In Mice Research Articles

Differential effects of 4‐aminopyridine on nerve injury severity‐dependent functional recovery and muscle atrophy in mice

Peripheral nerve injury (PNI) represents a major public health problem that often leads to profound neurologic impairment, disuse muscle atrophy, and permanent disability. While the functional recovery following nerve transection and repair is disappointing, the impact of irreparable nerve gap remains poorly characterized. Recently we demonstrated a repurposing beneficial effect of 4-aminopyridine (4-AP), a potassium channel blocker, on the functional recovery and muscle atrophy after sciatic nerve crush injury in rodents. However, this effect of 4-AP is unknown in nerve transection and gap models. This study was designed to evaluate and compare the functional recovery and muscle atrophy between nerve transection and nerve gap models in the absence (saline) and presence of 4-AP treatment. Under deep anesthesia and aseptic conditions, complete nerve transection or nerve gap injury was performed in male C57BL/6 mice (n = 10/group). In novel Stepwise Nerve Transection and Glue (STG) group, right sciatic nerve was sequentially transected with fibrin gluing to prevent gap formation. In nerve gap model, a large gap was created by dissecting out 7 mm (Gap-7) of right sciatic nerve section where the proximal stump of the nerve was buried underneath the muscle with fibrin glue. Following surgery, 4-AP (40 µg, ip) or saline was given daily and sciatic function index (SFI) was determined weekly for 12 weeks to evaluate functional recovery. After 12 weeks, tibialis anterior (TA) muscles were harvested for wet weight and histomorphological analysis. To asses muscle atrophy, right TA (RTA) muscle mass is presented as a percentage of contralateral healthy left TA (LTA) muscle which was assigned 100%. We found that SFI in STG group significantly dropped from baseline -9.9±2.83 to -66±2.24 (P<0.001) on one week followed by a small but significant recovery after 2 weeks (-51±4.42; P<0.05 vs. week-1) and then a steady state level between 9-12 weeks (-63±4.33). In Gap-7 group, SFI also significantly dropped from -8.5±3.18 to -72.4±2.50 in one week (P<0.001) and continued to deteriorate until it reached a steady state level after 10 weeks (-89.7±2.51). 4-AP had no effect on the SFI recovery in either group. Muscle atrophy was more pronounced in Gap-7 group (28±2% of LTA, P<0.001) compared to STG group (89±1.5% of LTA, P<0.001). Similar to muscle mass, RTA muscle cross sectional area (CSA) and minimum ferret diameter (MFD) were also significantly smaller in Gap-7 group compared to STG group. Interestingly, 4-AP treatment caused a significantly better recovery in RTA muscle mass, CSA, and MFD in Gap-7 group compared to STG group. These preliminary findings demonstrate that post-injury functional recovery and muscle atrophy after PNI are directly related to the intervening nerve gap, and 4-AP exerts differential effects on functional recovery and muscle atrophy.

Effect of Memantine Hydrochloride on Homocysteine Level and Cognitive Function in Diabetic Vascular Dementia Model Mice

Increased Hcy has a toxic effect on nerve cells and can cause hippocampal death and directly damage the body’s cognitive function and memory ability, leading to the occurrence of vascular dementia. Hcy predicts vascular disease and might be a basis for clinical judgment. This article provides a new basis for the prevention and treatment of this disease by exploring the mechanism of action of memantine hydrochloride in diabetic vascular dementia. After grouping, mice walked through the Morris water maze to record the escape latency, and measured the Hcy level of the mice by high performance liquid chromatography. Observing the volume of brain atrophy in mice. GFAPT, APP, and CHAT level in mouse hippocampus was assessed by IHC and CHAT mRNA was detected by RT-PCR. Escape latency, Hcy level (11.46 ±0.74) yiimmol/L, brain atrophy volume (25.21 ±1.21) mm3, number of APP positive cells (46.7003±3.2431), number of GFAP positive cells (21.4000 ± 1.8127) were all significantly lower than those of model group. The positive rate of CHAT and the amount of CHAT mRNA in the memantine hydrochloride group was significantly elevated (P &lt; 0.05) with higher CHAT mRNA than model group and lower than blank group (P &lt; 0.05). Memantine hydrochloride could reduce the level of Hcy in mice, improve the cognitive function of mice with diabetic vascular dementia by improving the number of GFAP and CHAT positive cells in hippocampus and cortex, and increasing the amount of CHAT mRNA in brain tissue.

Prenatal transplantation of human amniotic fluid stem cell could improve clinical outcome of type III spinal muscular atrophy in mice

Spinal muscular atrophy (SMA) is a single gene disorder affecting motor function in uterus. Amniotic fluid is an alternative source of stem cell to ameliorate SMA. Therefore, this study aims to examine the therapeutic potential of Human amniotic fluid stem cell (hAFSC) for SMA. Our SMA model mice were generated by deletion of exon 7 of Smn gene and knock-in of human SMN2. A total of 16 SMA model mice were injected with 1 × 105 hAFSC in uterus, and the other 16 mice served as the negative control. Motor function was analyzed by three behavioral tests. Engraftment of hAFSC in organs were assessed by flow cytometry and RNA scope. Frequency of myocytes, neurons and innervated receptors were estimated by staining. With hAFSC transplantation, 15 fetuses survived (93.75% survival) and showed better performance in all motor function tests. Higher engraftment frequency were observed in muscle and liver. Besides, the muscle with hAFSC transplantation expressed much laminin α and PAX-7. Significantly higher frequency of myocytes, neurons and innervated receptors were observed. In our study, hAFSC engrafted on neuromuscular organs and improved cellular and behavioral outcomes of SMA model mice. This fetal therapy could preserve the time window and treat in the uterus.

The effect of 10 weeks endurance training on protein levels of NF-kB and gene expression of Atrogin-1 and MuRF-1 in cardiac myocytes of female

Background: Cardiac atrophy is the most important complications resulted by cancer Given the role of exercise in protecting against cancer complications, the aim of the present study was to determine the effect of 10 weeks of endurance training on protein levels of NF-kB and gene expression of Atrogin-1 and MuRF-1 in cardiac myocyte of female Balb/C mic with breast cancer. Methods: The present study was an experimental study. Twelve female BALB/c mice after inducing breast cancer were randomly divided into two groups (n=6) including endurance training group (E) and the control group (C). E group performed 65 min at a constant running speed corresponding to 60% vVo2max at 15% inclination, ten weeks (five days a week). The Left ventricular of animals was extracted 24h following the last training session. Protein levels of NF-kB and gene expression of Atrogin-1 and MuRF-1 were determined by, respectively, western blot and qReal-time PCR. Statistic data values also were measured by independent samples t-test at the 0.05 levels of significance. Results: The results of the present study showed a significant decreased in cardiac protein levels of NF-kB (p&lt;0.001) and cardiac gene expression of Atrogin-1 (p&lt;0.001) and MuRF-1 (p=0.003) in comparison with control group. Endurance training group had significantly greater heart weights compared to control group (p&lt;0.001). Conclusion: it seems that 10 weeks of endurance training possibly affect mechanisms involved in cancer-induced cardiac atrophy such as NF-kB/Atrogin-1/MuRF-1 axis results in decreasing cardiac atrophy in mice with breast cancer.

PTEN in prefrontal cortex is essential in regulating depression-like behaviors in mice

Chronic stress is an environmental risk factor for depression and causes neuronal atrophy in the prefrontal cortex (PFC) and other brain regions. It is still unclear about the molecular mechanism underlying the behavioral alterations and neuronal atrophy induced by chronic stress. We here report that phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a mediator for chronic stress-induced depression-like behaviors and neuronal atrophy in mice. One-month chronic restraint stress (CRS) up-regulated PTEN signaling pathway in the PFC of mice as indicated by increasing levels of PTEN, p-MEK, and p-ERK but decreasing levels of p-AKT. Over-expression of Pten in the PFC led to an increase of depression-like behaviors, whereas genetic inactivation or knockdown of Pten in the PFC prevented the CRS-induced depression-like behaviors. In addition, systemic administration of PTEN inhibitor was also able to prevent these behaviors. Cellular examination showed that Pten over-expression or the CRS treatment resulted in PFC neuron atrophy, and this atrophy was blocked by genetic inactivation of Pten or systemic administration of PTEN inhibitor. Furthermore, possible causal link between Pten and glucocorticoids was examined. In chronic dexamethasone (Dex, a glucocorticoid agonist) treatment-induced depression model, increased PTEN levels were observed, and depression-like behaviors and PFC neuron atrophy were attenuated by the administration of PTEN inhibitor. Our results indicate that PTEN serves as a key mediator in chronic stress-induced neuron atrophy as well as depression-like behaviors, providing molecular evidence supporting the synaptic plasticity theory of depression.

Antagonistic control of myofiber size and muscle protein quality control by the ubiquitin ligase UBR4 during aging

Sarcopenia is a degenerative condition that consists in age-induced atrophy and functional decline of skeletal muscle cells (myofibers). A common hypothesis is that inducing myofiber hypertrophy should also reinstate myofiber contractile function but such model has not been extensively tested. Here, we find that the levels of the ubiquitin ligase UBR4 increase in skeletal muscle with aging, and that UBR4 increases the proteolytic activity of the proteasome. Importantly, muscle-specific UBR4 loss rescues age-associated myofiber atrophy in mice. However, UBR4 loss reduces the muscle specific force and accelerates the decline in muscle protein quality that occurs with aging in mice. Similarly, hypertrophic signaling induced via muscle-specific loss of UBR4/poe and of ESCRT members (HGS/Hrs, STAM, USP8) that degrade ubiquitinated membrane proteins compromises muscle function and shortens lifespan in Drosophila by reducing protein quality control. Altogether, these findings indicate that these ubiquitin ligases antithetically regulate myofiber size and muscle protein quality control.

First person – Frederike Riemslagh

ABSTRACTFirst Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Frederike Riemslagh is first author on ‘Inducible expression of human C9ORF72 36× G4C2 hexanucleotide repeats is sufficient to cause RAN translation and rapid muscular atrophy in mice’, published in DMM. Frederike conducted the research described in this article while a PhD Candidate in Prof. Dr Rob Willemse's lab at Erasmus Medical Center, Department of Clinical Genetics, Rotterdam, The Netherlands. She is now a Postdoctoral Fellow in the lab of Dr Christian Mosimann at the University of Colorado, USA, investigating genetic diseases that affect the heart and brain.

Inducible expression of human C9ORF72 36x G4C2 hexanucleotide repeats is sufficient to cause RAN translation and rapid muscular atrophy in mice.

ABSTRACTThe hexanucleotide G4C2 repeat expansion in the first intron of the C9ORF72 gene accounts for the majority of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) cases. Numerous studies have indicated the toxicity of dipeptide repeats (DPRs), which are produced via repeat-associated non-AUG (RAN) translation from the repeat expansion, and accumulate in the brain of C9FTD/ALS patients. Mouse models expressing the human C9ORF72 repeat and/or DPRs show variable pathological, functional and behavioral characteristics of FTD and ALS. Here, we report a new Tet-on inducible mouse model that expresses 36× pure G4C2 repeats with 100-bp upstream and downstream human flanking regions. Brain-specific expression causes the formation of sporadic sense DPRs aggregates upon 6 months of dox induction, but no apparent neurodegeneration. Expression in the rest of the body evokes abundant sense DPRs in multiple organs, leading to weight loss, neuromuscular junction disruption, myopathy and a locomotor phenotype within the time frame of 4 weeks. We did not observe any RNA foci or pTDP-43 pathology. Accumulation of DPRs and the myopathy phenotype could be prevented when 36× G4C2 repeat expression was stopped after 1 week. After 2 weeks of expression, the phenotype could not be reversed, even though DPR levels were reduced. In conclusion, expression of 36× pure G4C2 repeats including 100-bp human flanking regions is sufficient for RAN translation of sense DPRs, and evokes a functional locomotor phenotype. Our inducible mouse model suggests that early diagnosis and treatment are important for C9FTD/ALS patients.This article has an associated First Person interview with the first author of the paper.

Depletion of gut microbiota induces skeletal muscle atrophy by FXR-FGF15/19 signalling

Background: Recent evidence indicates that host-gut microbiota crosstalk has nonnegligible effects on host skeletal muscle, yet gut microbiota-regulating mechanisms remain obscure. Methods: C57BL/6 mice were treated with a cocktail of antibiotics (Abx) to depress gut microbiota for 4 weeks. The profiles of gut microbiota and microbial bile acids were measured by 16S rRNA sequencing and ultra-performance liquid chromatography (UPLC), respectively. We performed qPCR, western blot and ELISA assays in different tissue samples to evaluate FXR-FGF15/19 signaling. Results: Abx treatment induced skeletal muscle atrophy in mice. These effects were associated with microbial dysbiosis and aberrant bile acid (BA) metabolism in intestine. Ileal farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15) signaling was inhibited in response to microbial BA disturbance. Mechanistically, circulating FGF15 was decreased, which downregulated skeletal muscle protein synthesis through the extracellular-signal-regulated protein kinase 1/2 (ERK1/2) signaling pathway. Treating Abx mice with FGF19 (human FGF15 ortholog) partly reversed skeletal muscle loss. Conclusions: These findings indicate that the BA-FXR-FGF15/19 axis acts as a regulator of gut microbiota to mediate host skeletal muscle.

Matricaria chamomilla (Chamomile) Ameliorates Muscle Atrophy in Mice by Targeting Protein Catalytic Pathways, Myogenesis, and Mitochondrial Dysfunction.

Muscle atrophy, or loss of skeletal muscle, is caused by aging, malnutrition, immobility through injury, or diseases such as cancer. Chamomile (Matricaria chamomilla L.) contains various active components, including flavonoids, sesquiterpenes, polyacetylenes, and coumarins, and is used in various herbal medicines in the European Pharmacopoeia. In this study, we investigated the effects of ethanol extract of chamomile [Formula: see text](MC) on muscle wasting and its mechanism of action. Mice with dexamethasone (DEX)-induced muscle atrophy were orally administered MC (100, 200, and 300 mg/kg) for 4 weeks. Micro-computed tomography analysis showed that MC (200 and 300 mg/kg) significantly recovered DEX-induced loss of muscle volume, density, and weight and MC-treated DEX-induced mice also showed increased moving distance and grip strength. MC suppressed the mRNA level of muscle RING finger 1 (MuRF1) while increasing the expression of mitochondrial transcription factor A (TFAM), MyoD, and Myogenin-1. We found 25 peaks in MC samples through HPLC analysis and identified 6 peaks by comparison with a profile of standard compounds: chlorogenic acid (CGA), luteolin-7-O-glucoside (L7G), patulitrin, apigenin-7-O-glucoside (A7G), herniarin, and (E)-tonghaosu. Of these components, the gene expression of MyoD was significantly augmented by patulitrin, herniarin, CGA, and L7G in C2C12 cells, while Myogenin-1 gene expression was increased by A7G, patulitrin, herniarin, CGA, and L7G. Moreover, TFAM gene expression and phosphorylation of AKT were increased by all six ingredients. Based on our results, we suggest MC for use as a supplement or remedy for muscle wasting, including cachexia and sarcopenia.

Effects of electroacupuncture on proangiogenesis process and protein turnover in a mouse model of sarcopenia

To observe the effect of electroacupuncture(EA) on proangiogenesis process and protein turn-over in a mouse model of sarcopenia, so as to explore its potential molecular mechanism anti-aging. Fourteen 30-week-old male SAMP8 mice were randomly divided into a model group (n=7) and an EA group (n=7). Seven anti-rapidly aging SAMR1 mice of the same age were used as the control group (n=7). EA (1 mA, 4 Hz) was applied to bilateral "Zusanli"(ST36) and "Yanglingquan"(GB34) for 20 minutes each time once a day, 6 times a week for 4 weeks. The exhausted running platform was used to test the sports function. Gastrocnemius muscle mass and relative ratio of gastrocnemius muscle mass to body mass were measured. HE staining and transmission electron microscope were used to observe the morphology, and the cross-sectional area of gastrocnemius muscle was calculated. Relative protein expressions of protein kinase B (AKT) , phosphorylated (p) -AKT, mammalian target of rapamycin (mTOR) , p-mTOR, p70 ribosomal protein S6 kinase (p70S6K) , p-p70S6K,hypoxia inducible factor-1α (HIF-1α) and relative mRNA expressions of HIF-1α, vascular endothelial growth factor A (VEGF-A) , muscle RING finger-1 (MuRF-1) and muscle atrophy F-box (MAFbx) were detected by Western blot and real-time fluorescence quantitative PCR, seperatively. Compared with the control group, the running time and distance, body mass and gastrocnemius mass, and the ratio of gastrocnemius mass to body mass decreased(P<0.01, P<0.05), cross-sectional area of gastrocnemius, related protein expression of p-AKT,p-mTOR, p-p70S6K and HIF-1α, mRNA expression of HIF-1α and VEGF-A decreased (P<0.01), while mRNA expression of MuRF1 and MAFbx increased (P<0.01) in the model group. Following EA intervention, the running time and distance, body mass and gastrocnemius mass and the ratio of gastrocnemius mass to body mass increased (P<0.05), cross-sectional area of gastrocnemius, related protein expression of p-AKT,p-mTOR, p-p70S6K and HIF-1α, mRNA expression of HIF-1α and VEGF-A were significantly up-regulated (P<0.01), mRNA expression of MuRF1 and MAFbx down-regulated (P<0.01, P<0.05) in the EA group compared with the model group. EA may delay the aging muscle atrophy in mice by regulating the gastrocnemius muscle's proangiogenesis process and protein turnover.

Food restriction reduces cortical bone mass and serum insulin-like growth factor-1 levels and promotes uterine atrophy in mice

Low energy availability in female athletes often causes hypothalamic amenorrhea and osteoporosis, in turn promoting stress fractures. Mechanisms underlying these conditions remain unclear. Here we show that model mice subjected to food restriction (FR) or FR-plus-voluntary running exercise exhibit significantly reduced bone mineral density, cortical bone parameters and uterine weight than do control mice, and that these parameters worsen in the FR-plus-exercise group. Relative to controls, FR and FR-plus-exercise groups showed significantly lower mineral apposition rate and osteoclast number and significantly reduced serum insulin-like growth factor-1 (IGF1) levels. Outcomes were rescued by ED71 or 1.25(OH)2D3 treatment. Thus, we conclude that administration of active vitamin D analogues represents a possible treatment to prevent these conditions.

Oleamide rescues tibialis anterior muscle atrophy of mice housed in small cages.

Skeletal muscle atrophy causes decreased physical activity and increased risk of metabolic diseases. We investigated the effects of oleamide (cis-9,10-octadecanamide) treatment on skeletal muscle health. The plasma concentration of endogenous oleamide was approximately 30 nm in male ddY mice under normal physiological conditions. When the stable isotope-labelled oleamide was orally administered to male ddY mice (50 mg/kg), the plasma concentration of exogenous oleamide reached approximately 170 nm after 1 h. Male ddY mice were housed in small cages (one-sixth of normal size) to enforce sedentary behaviour and orally administered oleamide (50 mg/kg per d) for 4 weeks. Housing in small cages decreased tibialis anterior (TA) muscle mass and the cross-sectional area of the myofibres in TA muscle. Dietary oleamide alleviated the decreases in TA muscle and resulted in plasma oleamide concentration of approximately 120 nm in mice housed in small cages. Housing in small cages had no influence on the phosphorylation levels of Akt serine/threonine kinase (Akt), mechanistic target of rapamycin (mTOR) and ribosomal protein S6 kinase (p70S6K) in TA muscle; nevertheless, oleamide increased the phosphorylation levels of the proteins. Housing in small cages increased the expression of microtubule-associated protein 1 light chain 3 (LC3)-II and sequestosome 1 (p62), but not LC3-I, in TA muscle, and oleamide reduced LC3-I, LC3-II and p62 expression levels. In C2C12 myotubes, oleamide increased myotube diameter at ≥100 nm. Furthermore, the mTOR inhibitor, Torin 1, suppressed oleamide-induced increases in myotube diameter and protein synthesis. These results indicate that dietary oleamide rescued TA muscle atrophy in mice housed in small cages, possibly by activating the phosphoinositide 3-kinase/Akt/mTOR signalling pathway and restoring autophagy flux.

A Diet Including Red Bell Pepper Juice and Soy Protein Suppress Physiological Markers of Muscle Atrophy in Mice.

Although muscle atrophy can be caused by disuse and lifestyle-related syndromes, it may be possible to prevent this condition through dietary intervention. We hypothesized that a diet including red bell pepper juice (RBPJ) and soy protein isolate (SPI) would prevent muscle atrophy. Accordingly, an experimental diet containing RBPJ and/or SPI was administered for 18 d to normal C57BL/6J mice. The control group was administered a casein diet. Four days before the end of the test period, denervation-induced muscle atrophy and/or sham operation were performed. Anterior tibialis muscle samples were then obtained to assess muscle degradation and perform metabolome analysis. Under the denervation condition, the 20% SPI diet did not alter the mRNA expression levels of muscle atrophy marker genes compared with the 20% casein group. Although the diet comprising RBPJ and 20% casein did not prevent muscle atrophy compared with the control group, the diet containing RBPJ and 20% SPI did. Metabolome analysis revealed that a diet including RBPJ and SPI induced a greater than 1.5-fold change in the levels of 20 muscle atrophy-related metabolites. In particular, the level of S-adenosylmethionine, which concerned with energy metabolism and lifespan, showed a strong positive correlation with the muscle atrophy marker. These findings suggest that a diet including RBPJ and soy protein suppress gene expressions related with muscle atrophy. Further research in humans is needed to confirm whether a combination of RBPJ and SPI can indeed prevent muscle atrophy.

Irisin Correlates Positively With BMD in a Cohort of Older Adult Patients and Downregulates the Senescent Marker p21 in Osteoblasts.

Irisin is a myokine produced by skeletal muscle during exercise in both mice and humans. We previously showed that irisin treatment ameliorates immobility-induced osteoporosis and muscular atrophy in mice. Data in humans showed a positive association between irisin and bone mineral density (BMD) in athletes and a population of healthy children. However, the role of this myokine regarding the state of muscle and bone in the same population remained to be determined. For this purpose, 62 patients (age 68.71 ± 12.31 years) undergoing total hip or knee replacement were recruited. Our results showed that irisin serum levels negatively correlated with age (R = -0.515; p = .000018) and positively correlated with femoral BMD (R = 0.619; p = .001) and vertebral BMD (R = 0.201; p = .0001). Irisin was also positively associated with Fndc5 mRNA in muscle biopsies (R = 0.248; p = .016), as well as with Osteocalcin (Ocn) mRNA in bone biopsies (R = 0.708; p = .006). In skeletal muscle, FNDC5 positive fibers positively correlate with BMD of total femur (R = 0.765; p = .0014) and BMD of femoral neck (R = 0.575; p = .031), Interestingly, by analyzing patients divided by their T-score, we found lower irisin levels (p = .0011) in patients with osteopenia/osteoporosis (OP) compared to healthy controls matched for age and sex. By analyzing the senescence marker p21, we found a significant increase of its mRNA expression in the bone biopsies of OP patients compared to control ones. Therefore, we investigated in vitro whether rec-irisin had a direct effect on this senescence marker, showing that p21 mRNA expression was significantly downregulated in osteoblasts by the treatment with irisin. Overall, these results indicate that higher irisin levels are associated with a lower rate of age-related osteoporosis and that irisin could be effective in delaying the osteoblast aging process, suggesting a potential senolytic action of this myokine. © 2020 American Society for Bone and Mineral Research (ASBMR).

T. gondii infection induces IL-1R dependent chronic cachexia and perivascular fibrosis in the liver and skeletal muscle

Cachexia is a progressive muscle wasting disease that contributes to death in a wide range of chronic diseases. Currently, the cachexia field lacks animal models that recapitulate the long-term kinetics of clinical disease, which would provide insight into the pathophysiology of chronic cachexia and a tool to test therapeutics for disease reversal. Toxoplasma gondii (T. gondii) is a protozoan parasite that uses conserved mechanisms to infect rodents and human hosts. Infection is lifelong and has been associated with chronic weight loss and muscle atrophy in mice. We have recently shown that T. gondii-induced muscle atrophy meets the clinical definition of cachexia. Here, the longevity of the T. gondii-induced chronic cachexia model revealed that cachectic mice develop perivascular fibrosis in major metabolic organs, including the adipose tissue, skeletal muscle, and liver by 9 weeks post-infection. Development of cachexia, as well as liver and skeletal muscle fibrosis, is dependent on intact signaling through the type I IL-1R receptor. IL-1α is sufficient to activate cultured fibroblasts and primary hepatic stellate cells (myofibroblast precursors in the liver) in vitro, and IL-1α is elevated in the sera and liver of cachectic, suggesting a mechanism by which chronic IL-1R signaling could be leading to cachexia-associated fibrosis.

Vitamin D protects against immobilization-induced muscle atrophy via neural crest-derived cells in mice

Vitamin D deficiency is a recognized risk factor for sarcopenia development, but mechanisms underlying this outcome are unclear. Here, we show that low vitamin D status worsens immobilization-induced muscle atrophy in mice. Mice globally lacking vitamin D receptor (VDR) exhibited more severe muscle atrophy following limb immobilization than controls. Moreover, immobilization-induced muscle atrophy was worse in neural crest-specific than in skeletal muscle-specific VDR-deficient mice. Tnfα expression was significantly higher in immobilized muscle of VDR-deficient relative to control mice, and was significantly elevated in neural crest-specific but not muscle-specific VDR-deficient mice. Furthermore, muscle atrophy induced by limb immobilization in low vitamin D mice was significantly inhibited in Tnfα-deficient mice. We conclude that vitamin D antagonizes immobilization-induced muscle atrophy via VDR expressed in neural crest-derived cells.

S-allyl cysteine: A potential compound against skeletal muscle atrophy

BackgroundOxidative stress is crucial player in skeletal muscle atrophy pathogenesis. S-allyl cysteine (SAC), an organosulfur compound of Allium sativum, possesses broad-spectrum properties including immuno- and redox-modulatory impact. Considering the role of SAC in regulating redox balance, we hypothesize that SAC may have a protective role in oxidative-stress induced atrophy. MethodsC2C12 myotubes were treated with H2O2 (100 μM) in the presence or absence of SAC (200 μM) to study morphology, redox status, inflammatory cytokines and proteolytic systems using fluorescence microscopy, biochemical analysis, real-time PCR and immunoblotting approaches. The anti-atrophic potential of SAC was confirmed in denervation-induced atrophy model. ResultsSAC pre-incubation (4 h) could protect the myotube morphology (i.e. length/diameter/fusion index) from atrophic effects of H2O2. Lower levels of ROS, lipid peroxidation, oxidized glutathione and altered antioxidant enzymes were observed in H2O2-exposed cells upon pre-treatment with SAC. SAC supplementation also suppressed the rise in cytokines levels (TWEAK/IL6/myostatin) caused by H2O2. SAC treatment also moderated the degradation of muscle-specific proteins (MHCf) in the H2O2-treated myotubes supported by lower induction of diverse proteolytic systems (i.e. cathepsin, calpain, ubiquitin-proteasome E3-ligases, caspase-3, autophagy). Denervation-induced atrophy in mice illustrates that SAC administration alleviates the negative effects (i.e. mass loss, decreased cross-sectional area, up-regulation of proteolytic systems, and degradation of total/specific protein) of denervation on muscles. ConclusionsSAC exerts significant anti-atrophic effects to protect myotubes from H2O2-induced protein loss and myofibers from denervation-induced muscle loss, due to the prevention of elevated proteolytic systems and inflammatory/oxidative molecules. General significanceThe results signify the potential of SAC against muscle atrophy.

Inorganic Arsenic Exposure Decreases Muscle Mass and Enhances Denervation-Induced Muscle Atrophy in Mice.

Arsenic is a toxic metalloid. Infants with a low birth-weight have been observed in areas with high-level arsenic in drinking water ranging from 463 to 1025 μg/L. A distal muscular atrophy side effect has been observed in acute promyelocytic leukemia patients treated with arsenic trioxide (As2O3) for therapy. The potential of As2O3 on muscle atrophy remains to be clarified. In this study, the myoatrophic effect of arsenic was evaluated in normal mice and sciatic nerve denervated mice exposed with or without As2O3 (0.05 and 0.5 ppm) in drinking water for 4 weeks. We found that both 0.05 and 0.5 ppm As2O3 increased the fasting plasma glucose level; but only 0.5 ppm arsenic exposure significantly decreased muscle mass, muscle endurance, and cross-sectional area of muscle fibers, and increased muscle Atrogin-1 protein expression in the normal mice. Both 0.05 and 0.5 ppm As2O3 also significantly enhanced the inhibitory effects on muscle endurance, muscle mass, and cross-sectional area of muscle fibers, and increased the effect on muscle Atrogin-1 protein expression in the denervated mice. These in vivo results suggest that inorganic arsenic at doses relevant to humans may possess myoatrophic potential.

Involvement of receptor for advanced glycation end products in microgravity-induced skeletal muscle atrophy in mice

The accumulation of advanced glycation end-products (AGEs) may be involved in the mechanism of skeletal muscle atrophy. However, the involvement of the receptor for AGEs (RAGE) axis in microgravity-induced skeletal muscle atrophy has not been investigated. Therefore, the purpose of the present study was to investigate the effect of RAGE inhibition on microgravity-induced skeletal muscle atrophy and the related molecular responses. Male C57BL/6NCr mice subjected to a 1-week hindlimb suspension lead to muscle atrophy in soleus and plantaris but not extensor digitorum longus muscle, accompanied by increases in RAGE expression. However, treatment with a RAGE antagonist (FPS-ZM1, intraperitoneal, 1 mg/kg/day) during hindlimb suspension ameliorated the atrophic responses in soleus muscle. Further, muscle mass inversely correlated with the accumulation of AGEs (methylglyoxal-modified proteins and Nε-(carboxymethyl) lysine-modified proteins) in soleus muscle. The expression of proinflammatory cytokines, tumor necrosis factor-α, interleukin-1β, and interleukin-6 in soleus muscle was enhanced in response to hindlimb suspension, but these changes were attenuated by FPS-ZM1 treatment. Protein ubiquitination and ubiquitin E3 ligase (muscle RING finger 1) expression in soleus muscle were elevated following hindlimb suspension, and these increments were suppressed by FPS-ZM1 treatment. Our findings indicate that the AGE-RAGE axis is upregulated in unloaded atrophied skeletal muscle, and that RAGE inhibition ameliorates microgravity-induced skeletal muscle atrophy by reducing proinflammatory cytokine expression and ubiquitin-proteasome system activation.