Apoptosis In Skeletal Muscle Research Articles

Embryonic stem cell-derived mesenchymal stem cells alleviate skeletal muscle injury induced by acute compartment syndrome

BackgroundAcute compartment syndrome (ACS), a well-known complication of musculoskeletal injury, results in muscle necrosis and cell death. Embryonic stem cell-derived mesenchymal stem cells (ESC-MSCs) have been shown to be a promising therapy for ACS. However, their effectiveness and potentially protective mechanism remain unknown. The present study was designed to investigate the efficacy and underlying mechanism of ESC-MSCs in ACS-induced skeletal muscle injury.MethodA total of 168 male Sprague–Dawley (SD) rats underwent 2 h of intracompartmental pressure elevation by saline infusion into the anterior compartment of the left hindlimb to establish the ACS model. ESC-MSCs were differentiated from the human embryonic stem cell (ESC) line H9. A dose of 1.2 × 106 of ESC-MSCs was intravenously injected during fasciotomy. Post-ACS assessments included skeletal edema index, serum indicators, histological analysis, apoptosis, fibrosis, regeneration, and functional recovery of skeletal muscle. Then, fluorescence microscopy was used to observe the distribution of labeled ESC-MSCs in vivo, and western blotting and immunofluorescence analyses were performed to examine macrophages infiltration in skeletal muscle. Finally, we used liposomal clodronate to deplete macrophages and reassess skeletal muscle injury in response to ESC-MSC therapy.ResultESC-MSCs significantly reduced systemic inflammatory responses, ACS-induced skeletal muscle edema, and cell apoptosis. In addition, ESC-MSCs inhibited skeletal muscle fibrosis and increased regeneration and functional recovery of skeletal muscle after ACS. The beneficial effects of ESC-MSCs on ACS-induced skeletal muscle injury were accompanied by a decrease in CD86-positive M1 macrophage polarization and an increase in CD206-positive M2 macrophage polarization. After depleting macrophages with liposomal clodronate, the beneficial effects of ESC-MSCs were attenuated.ConclusionOur findings suggest that embryonic stem cell-derived mesenchymal stem cells infusion could effectively alleviate ACS-induced skeletal muscle injury, in which the beneficial effects were related to the regulation of macrophages polarization.

Aerobic exercise prevents apoptosis in skeletal muscles of high-fat-fed ovariectomized rats.

[Purpose] Aging and obesity are associated with skeletal muscle atrophy-related signaling pathways, including apoptosis. Many studies have shown that menopause is associated with an increased risk of skeletal muscle atrophy. There is an increasing need to develop strategies that will improve the risk of skeletal muscle atrophy through exercise interventions. However, the effect of exercise on estrogen deficiency-induced apoptosis in skeletal muscles is poorly understood. Therefore, we examined the effects of low-intensity exercise on ovariectomy (OVX)-induced apoptosis of the soleus and plantaris muscles.[Methods] The ovaries of all female Sprague-Dawley rats aged 8 weeks, were surgically removed to induce postmenopausal status. The rats were randomly divided into three treatment groups: (1) NSV (normal-diet-sedentary-OVX); (2) HSV (high-fat-diet-sedentary-OVX); and (3) HEV (high-fat-diet-exercise-OVX). The exercise groups were regularly running for 30-40 min/day at 15-18 m/minute, five times/week, for eight weeks.[Results] The mRNA levels of Bax significantly decreased in the exercised soleus muscle, and caspase-3 decreased in the plantaris. The skeletal muscle TUNEL-positive apoptotic cells in the high-fat-diet-sedentary OVX rats improved in the treadmill exercise group. Additionally, nuclear caspase-3 levels decreased in the treadmill exercise group compared to those in both sedentary groups. These results suggest that low-intensity treadmill exercise prevents skeletal muscle apoptosis in HFD-fed OVX rats.[Conclusion] Induction of HFD in estrogen-deficient mice increased apoptosis in skeletal muscle, which could also be alleviated by low-intensity aerobic exercise. These results may indicate a crucial therapeutic effect of treadmill exercise in preventing skeletal muscle apoptosis in menopausal or post-menopausal women.

운동 형태에 따른 노화 쥐 골격근 내 Apoptosis 작용기전에 미치는 영향

The purpose of this study is to investigate the effect of exercise type on the mechanism of apoptosis in the skeletal muscle of aging mice.BR For the experiment, it was classified into a young group (n=10), an aging group (n=10), an uphill exercise(n=10), and a downhill exercise(n=10). The exercise group performed treadmill exercises for 60 minutes, five days a week and eight weeks at exercise intensity 13 m/min, slope 10° (uphill excise) and eccentric excise 23 m/min, -16° (downhill excise).BR The results of this study are as follows.BR 1. Two forms of endurance training in skeletal muscle building in aging mice and changes in expression of oxidative stress-related factors have had a positive effect on aging mice.BR 2. In changes in expression of factors related to apoptosis in skeletal muscle and interaction of IGFBP-3 in aging mice, two forms of endurance exercise training had a positive effect on aging mice.BR 3. In changes in expression of factors related to cell growth and differentiation in skeletal muscle in aging mice and the interaction-related factors of IGFBP-3, two forms of endurance exercise training had a positive effect on aging mice.BR Therefore, the expression mechanism of IGFBP-3, a key factor of stress caused by exercise, not only presented academically meaningful results but also presented important data to suggest safer exercise methods.

Effects of Regular and Continuous Exercise on Oxidative Stress and Apoptosis

In this study, it was aimed to investigate the effects of intense acute exercise and regular and continuous exercise on oxidative stress parameters and apoptosis-related Bax and Bcl-2 protein levels in rats. In the study, 1 control and 4 experimental groups were formed from 35 male Wistar-Albino rats, 7 in each group. The control group was not exercised, the other four groups exercised at a speed of 1.5 km/h for 1 hour on a 20 degree incline treadmill every day. Control and 1st group at the end of the 1st day, 2nd group 7th day, 3rd group 15th day and 4th group 30th day were sacrificed under anesthesia. Malondialdehyde (MDA) as an indicator of lipid peroxidation, and Glutathione (GSH), Catalase (CAT), Glutathione Peroxidase (GSH-Px) levels as an antioxidant indicator in muscle and plasma levels were measured. Bax and Bcl-2 protein expression levels were also checked for apoptosis in skeletal muscle. According to the results obtained, skeletal muscle and plasma MDA values increased after acute exercise (P<0.05), while skeletal muscle and plasma GSH-Px, CAT values increased significantly after continuing regular and continuous exercise (P<0.01). It was observed that Bax protein expression level increased, Bcl-2 protein expression level decreased and Bax/Bcl-2 ratio increased in acute exercise (p<0.05). As a result, it was concluded that regular and continuous exercise has a protective effect against oxidative stress and apoptosis triggered by acute exercise can be suppressed by regular and continuous exercise.

Role of VEGFB in electrical pulse stimulation inhibits apoptosis in C2C12 myotubes

Skeletal muscle is the major effector organ for exercise. It has been proposed that VEGFB is significantly related to apoptosis in various cell types but not yet in skeletal muscle. We hypothesize that the decrease of VEGFB in skeletal muscle participates in the occurrence of skeletal muscle apoptosis and that exercise inhibits apoptosis by elevating the expression of VEGFB in skeletal muscle cells. Based on this hypothesis, we developed in vitro experiments to mimic the effect of exercise through electrical pulse stimulation (EPS) to observe the effect of EPS on apoptosis and the change in VEGFB expression in differentiated myotubes. In addition, we employed RNA interference to explore whether VEGFB is directly involved in the regulation of myotube apoptosis during EPS. Our results showed that exogenous VEGFB167 significantly inhibited C2C12 myotube apoptosis induced by TNF-α treatment and that endogenous VEGFB in differentiated C2C12 myotubes was significantly upregulated by EPS. In addition, EPS significantly changed the expression of the apoptotic indicators Bax and Bcl-2 at the mRNA level and downregulated the protein expression of cleaved caspase-3. The antiapoptotic effect of EPS weakened substantially as VEGFB in C2C12 myotubes was inhibited. Taken together, these results indicate that exercise-like EPS inhibits apoptosis by increasing the expression of C2C12 myotube-derived VEGFB.

Heat shock protein A4 ablation leads to skeletal muscle myopathy associated with dysregulated autophagy and induced apoptosis

BackgroundMolecular chaperones assist protein folding, facilitate degradation of misfolded polypeptides, and thereby maintain protein homeostasis. Impaired chaperone activity leads to defective protein quality control that is implicated in multiple skeletal muscle diseases. The heat shock protein A4 (HSPA4) acts as a co-chaperone for HSP70. Previously, we showed that Hspa4 deletion causes impaired protein homeostasis in the heart. However, its functional role in skeletal muscle has not been explored.MethodsWe performed a comparative phenotypic and biochemical analyses of Hspa4 knockout (KO) mice with wild-type (WT) littermates.ResultsHSPA4 is markedly upregulated in regenerating WT muscle in vivo, and in differentiated myoblasts in vitro. Hspa4-KO mice are marked by growth retardation and increased variability in body weight, accompanied by 35% mortality rates during the peri-weaning period. The surviving Hspa4-KO mice experienced progressive skeletal muscle myopathy, characterized by increased number of muscle fibers with centralized nuclei, heterogeneous myofiber size distribution, inflammatory cell infiltrates and upregulation of embryonic and perinatal myosin heavy chain transcripts. Hspa4-KO muscles demonstrated an accumulation of autophagosome-associated proteins including microtubule associated protein1 light chain 3-II (LC3-II) and p62/sequestosome accompanied by increased number of TUNEL-positive nuclei.ConclusionsOur findings underscore the indispensable role of HSPA4 in maintenance of muscle integrity through contribution in skeletal muscle autophagy and apoptosis, which might provide a novel therapeutic strategy for skeletal muscle morbidities.

Di-(2-ethyl hexyl) phthalate induced oxidative stress promotes microplastics mediated apoptosis and necroptosis in mice skeletal muscle by inhibiting PI3K/AKT/mTOR pathway

The plastic decomposition product microplastics (MPs) and the plastic additive Di (2-ethylhexyl) phthalate (DEHP) in the environment can damage various organs of the organism by inducing oxidative stress. The PI3K/AKT/mTOR signaling pathway participate in toxin-induced apoptosis and necroptosis. However, the effects of DEHP/MPs alone and combined exposure on skeletal muscle cell injury in mice and the role of PI3K/AKT/mTOR axis remain unclear. To investigate the effect of DEHP or/and MPs on skeletal muscle in mice and its possible toxicological mechanism, 60 mice were randomly divided into control group, DEHP group (DEHP 200 mg/kg dissolved in 50 mL corn oil mixed with 2.5 kg diet), MPs group (10 mg/L MPs in drinking water) and combined exposure group. In vitro, C2C12 cells were exposed to DEHP 600 μM/MPs 800 μM alone or in combination for 24 h. The results showed that DEHP/MPs exposure alone or in combination increased MDA content, decreased activities of CAT, T-AOC, SOD and GSH-Px, increased mRNA and protein expressions of Caspase-3, BAX, RIPK1, RIPK3 and MLKL, and decreased BCL-2 expression. The expression of PI3K/AKT/mTOR signaling pathway was significantly down-regulated. All the above results showed that the combined exposure group was more toxic, and similar experimental results were obtained by DEHP/MPs exposure test of C2C12 cells in vitro. It is suggested that DEHP/MPs can induce apoptosis and necroptosis by activating oxidative stress and down-regulating PI3K/AKT/mTOR pathway. This study provides new evidence for clarifying the possible mechanism of toxicity of DEHP and MPs to skeletal muscle of mice.

The mechanism of immune related signal pathway Egr2-FasL-Fas in transcription regulation and methylated modification of Paralichthys olivaceus under acute hypoxia stress

Apoptosis genes Egr2, Fas and FasL are related to immune responses. However, the mechanism of these genes inducing apoptosis in fish are still not very clear. An acute hypoxia treatment (1.73 ± 0.06 mg/L) for 24 h was carried out on Japanese flounder (Paralichthys olivaceus). The increasingly dense apoptotic signals at 3 h, 6 h, 12 h by TUNEL in skeletal muscle indicated that hypoxia could quickly affect muscle growth and development. Furthermore, we concluded that the Egr2-FasL-Fas signal pathway, which was located at the upstream of apoptotic executor protein caspases, was related to the apoptosis by quantitative real-time PCR, protein concentration detection in ELISA and double gene in situ hybridization methods. The mechanism of the pathway was researched in transcription regulation and epigenetic modification by dual-luciferase reporter assay and bisulfite modified method, respectively. Egr2, as a transcription factor, could up-regulate the expression of FasL gene. And its binding site was mainly between −479 to −1 of FasL gene promoter. The 5th CpG dinucleotides (−514) methylation levels in FasL gene were significantly affected by hypoxia, and they were negatively correlated with its expressions. These suggested that the −514 site may be a very important site to regulate the FasL gene expression. Above results, we concluded that hypoxia activated the immune related signal pathway Egr2-FasL-Fas to induced skeletal muscle apoptosis to affect growth and development of Japanese flounder. The study revealed the mechanism of hypoxia induced apoptosis, which could provide a reference for fish immunity and aquaculture management.

Exercise Capacity Is Improved by Levosimendan in Heart Failure and Sarcopenia via Alleviation of Apoptosis of Skeletal Muscle.

BackgroundPatients suffering from chronic heart failure (CHF) show an increased prevalence of sarcopenia. Levosimendan is an effective drug for the treatment of heart failure, but its effect on sarcopenia is still unclear. We aimed to explore whether levosimendan could enhance skeletal muscle contractibility, improve skeletal muscle atrophy, and thus improve exercise tolerance of individuals with heart failure.MethodsC57BL6/J mice were used to establish the heart failure with sarcopenia model and injected of levosimendan. Mice were separated into control group, sham operation group, HF group, HF + solvent group, HF + levosimendan group, HF + sarcopenia group, HF + sarcopenia + solvent group, HF + sarcopenia + levosimendan group (n = 5–12). After the treatment, exercise capacity and cardiac function were evaluated. Muscle morphology, inflammation level and apoptosis levels were detected, in which mitochondrial function and oxidative stress level were also assessed.ResultLevosimendan could increase forelimb grip strength/body weight, hanging impulse, maximum running distance and time in mice with HF and sarcopenia (P < 0.0001 for all), and these improvements were independent of EF (P = 0.0019 for hanging impulse, P < 0.001 for forelimb grip strength/body weight and maximum running distance). Levosimendan directly increased the CSA of gastrocnemius in mice with HF and sarcopenia (P < 0.0001). After levosimendan injection, the proportion of slow muscle fibers increased (P < 0.0001), but this improvement of muscle fiber typing might be attributed to improved cardiac function (P > 0.05). Levosimendan also maintained mitochondrial membrane potential, decreased cleaved caspase-3 (P = 0.034), cleaved caspase-9 (P < 0.0001), Bax expression (P < 0.0001), and increased Bcl2 expression (P = 0.0036). This effect is independent of improved cardiac function (P = 0.028 for bax, P < 0.001 for cleaved caspase-9 and Bcl2). IL-6, TNF-α expression (P < 0.0001 for both) decreased, and SOD activity (P = 0.0038), GSH/GSSG ratio (P = 0.002) significantly increased in skeletal muscle after injection of levosimendan. The improvement in oxidative stress level was attributed to improved cardiac function (P > 0.05).ConclusionLevosimendan reduce the loss of skeletal muscle mitochondrial membrane potential, decrease the apoptosis, alleviate the inflammation and oxidative stress, and ultimately improve the exercise capacity of mice with heart failure and sarcopenia. Therefore, levosimendan may be a potential drug for the treatment of heart failure with sarcopenia.

Fermented Antler Recovers Stamina, Muscle Strength and Muscle Mass in Middle-Aged Mice

In a previous study, we found that Lactobacillus curvatus HY7602-fermented antler (FA) improved exercise endurance by increasement of muscle mass and strength in a young mouse model. In this study, we investigated the effect of FA on recovery of muscle mass and strength in aging-induced muscle loss. We have used a middle-aged model in which muscle decline begins in many mammalian species. All mice performed treadmill exercise and forced swimming, and measured muscle grip strength. Then, calf muscle weight and histological analysis, blood biomarker and gene expression in soleus muscle tissue were measured. Muscle strength and forced swimming time were significantly increased in the FA-intake groups compared to controls. The levels of muscle and liver damage-related indicators (ATL, ALP, LDH and CK) and muscle endurance, fatigue and exercise performance-related indicators (lactate and creatinine) were significantly improved by FA supplementation. In addition, FA regulates genes related to muscle protein degradation (Atrogin-1 and MuRF1) and muscle fiber synthesis (MyoD and Myf5), resulting in increased muscle mass, and fiber diameter and area values. The Bax/Bcl-2 ratio, related to apoptosis in skeletal muscle was significantly decreased. These results demonstrate that FA improves exercise performance with ameliorating blood biomarkers and also increases muscle mass and muscle strength by inhibiting muscle proteolysis and promoting muscle synthesis in a middle-aged mouse.

Exercise training and probiotic supplementation effects on skeletal muscle apoptosis prevention in type-Ι diabetic rats

AimsHyperglycemia occurring in the diabetic condition can cause apoptosis via the mitochondrial pathway with higher pro-apoptotic protein expression. Probiotics are viable microorganisms that have anti-diabetic and antioxidant effects. Also, exercise may affect the signaling pathways of skeletal muscle apoptosis. This study examined the aerobic exercise training and probiotic supplementation effects on some apoptotic indices of the soleus muscle in diabetic rats-induced by streptozotocin. Main methodsWe examined 32 male Wistar rats (weight: 250–270 g; age: eight weeks old) and divided them into four groups: control, control + probiotics, aerobic training (AT), and AT + probiotics (ATS). The rats in the training groups aerobically exercised using a treadmill five days per week for five weeks. We evaluated the gene expression of Bax, Bcl2, and p53 using the RT-PCR. We also used a one-way ANOVA for statistical analysis and set the significance level at P ≤ 0.05. Key findingsThe results showed that the fasting blood sugar was significantly higher in the control and control + probiotics groups (P = 0.008). Moreover, the AT + probiotics group showed lower expression of p53 (P = 0.005), Bax (P = 0.001) and the Bax/Bcl2 ratio (P = 0.001). Conversely, Bcl2 expression was higher after aerobic training and receiving probiotics (P = 0.002). However, the groups revealed no significant difference regarding muscle weight (P = 0.053) and the muscle weight/final body weight ratio of the rats (P = 0.26). SignificanceIt appears that aerobic exercise training with the use of probiotics prevents apoptosis in the muscle with the down-regulation of blood glucose.

Astaxanthin Protects Against Heat-induced Mitochondrial Alterations in Mouse Hypothalamus

The hypothalamus plays an essential role in regulating whole-body energy and temperature homeostasis when adapting to environmental changes. We previously reported that heat exposure causes mitochondrial dysfunction and apoptosis in mouse skeletal muscle, and pretreatment with astaxanthin (AST), an antioxidant, prevents this effect. How the hypothalamus responds to heat stress remains largely unexplored. In this study, we investigated the effects of heat exposure on hypothalamic mitochondria in mice with and without AST pretreatment. During heat exposure, both vehicle and AST-treated mice had a hyperthermic response though no significant differences in peak core body temperature were noted between the two groups. Heat exposure induced mitochondrial fission in the hypothalamus, as manifested by increased mitochondrial fragmentation and expression of both total and phosphorylated dynamin-related protein 1. In addition, transmission electron microscopy revealed damaged and degraded mitochondria in the hypothalamus of heat-exposed mice. Heat induced apoptosis and mitophagy were further confirmed by increased formation of reactive oxygen species, activation of caspase 3/7 and expression of LC3 proteins. Moreover, heat exposure increased the expression of PINK1 and Parkin in mouse hypothalamus. In contrast, pretreatment with AST reduced these effects. These results demonstrate that heat stress-induced hypothalamic apoptosis is associated with altered mitochondrial dynamics favoring fission and mitophagy. AST protects the hypothalamus against heat-induced injury by preserving redox homeostasis and mitochondrial integrity.

Ginsenoside compound K ameliorates palmitate-induced atrophy in C2C12 myotubes via promyogenic effects and AMPK/autophagy-mediated suppression of endoplasmic reticulum stress

BackgroundCompound K (CK) is among the protopanaxadiol (PPD)-type ginsenoside group, which produces multiple pharmacological effects. Herein, we examined the effects of CK on muscle atrophy under hyperlipidemic conditions along with its pro-myogenic effects. Further, the molecular pathways underlying the effects of CK on skeletal muscle have been justified. MethodsC2C12 myotubes were treated with palmitate and CK. C2C12 myoblasts were differentiated using CK for 4–5 days. For the in vivo experiments, CK was administered to mice fed on a high-fat diet for 8 weeks. The protein expression levels were analyzed using western blotting analysis. Target protein suppression was performed using small interfering (si) RNA transfection. Histological examination was performed using Jenner-Giemsa and H&E staining techniques. ResultsCK treatment attenuated ER stress markers, such as eIF2α phosphorylation and CHOP expression and impaired myotube formation in palmitate-treated C2C12 myotubes and skeletal muscle of mice fed on HFD. CK treatment augmented AMPK along with autophagy markers in skeletal muscle cells in vitro and in vivo experiments. AMPK siRNA or 3-MA, an autophagy inhibitor, abrogated the impacts of CK in C2C12 myotubes. CK treatment augmented p38 and Akt phosphorylation, leading to an enhancement of C2C12 myogenesis. However, AMPK siRNA abolished the effects of CK in C2C12 myoblasts. ConclusionThese findings denote that CK prevents lipid-induced skeletal muscle apoptosis via AMPK/autophagy-mediated attenuation of ER stress and induction of myoblast differentiation. Therefore, we may suggest the use of CK as a potential therapeutic approach for treating muscle-wasting conditions associated with obesity.

Wharton's Jelly-Derived Mesenchymal Stem Cells Reduce Fibrosis in a Mouse Model of Duchenne Muscular Dystrophy by Upregulating microRNA 499.

The aim of this study was to evaluate the therapeutic effects and mechanisms of Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) in an animal model of Duchenne muscular dystrophy (DMD). Mdx mice (3–5 months old) were administered five different doses of WJ-MSCs through their tail veins. A week after injection, grip strength measurements, creatine kinase (CK) assays, immunohistochemistry, and western blots were performed for comparison between healthy mice, mdx control mice, and WJ-MSC-injected mdx mice. WJ-MSCs exerted dose-dependent multisystem therapeutic effects in mdx mice, by decreasing CK, recovering normal behavior, regenerating muscle, and reducing apoptosis and fibrosis in skeletal muscle. We also confirmed that miR-499-5p is significantly downregulated in mdx mice, and that intravenous injection of WJ-MSCs enhanced its expression, leading to anti-fibrotic effects via targeting TGFβR 1 and 3. Thus, WJ-MSCs may represent novel allogeneic “off-the-shelf” cellular products for the treatment of DMD and possibly other muscle disorders.

Administration of tauroursodeoxycholic acid attenuates dexamethasone-induced skeletal muscle atrophy

Glucocorticoids are known to induce skeletal muscle atrophy by suppressing protein synthesis and promoting protein degradation. Tauroursodeoxycholic acid (TUDCA) has beneficial effects in several diseases, such as hepatobiliary disorders, hindlimb ischemia and glucocorticoid-induced osteoporosis. However, the effects of TUDCA on glucocorticoid -induced skeletal muscle atrophy remains unknown. Therefore, in the present research, we explored the effects of TUDCA on dexamethasone (DEX)-induced loss and the potential mechanisms involved. We found TUDCA alleviated DEX-induced muscle wasting in C2C12 myotubes, identified by improved myotube differentiation index and expression of myogenin and MHC. And it showed that TUDCA activated the Akt/mTOR/S6K signaling pathway and inhibited FoxO3a transcriptional activity to decreased expression of MuRF1 and Atrogin-1, while blocking Akt by MK2206 blocked these effects of TUDCA on myotubes. Besides, TUDCA also attenuated DEX-induced apoptosis of myotubes. Furthermore, TUDCA was administrated to the mouse model of DEX-induced skeletal muscle atrophy. The results showed that TUDCA improved DEX-induced skeletal muscle atrophy and weakness (identified by increased grip strength and prolonged running exhaustive time) in mice by suppression of apoptosis, reduction of protein degradation and promotion of protein synthesis. Taken together, our research proved for the first time that TUDCA protected against DEX-induced skeletal muscle atrophy not only by improving myogenic differentiation and protein synthesis, but also through decreasing protein degradation and apoptosis of skeletal muscle.

Pet Therapy as a Nonpharmacological Treatment Option for Neurological Disorders: A Review of the Literature.

Animal therapy and ownership have been studied as a nonpharmacologic treatment option for cardiovascular and psychological disorders. Animal companionship is less studied in neurological disorders such as stroke, dementia, Parkinson’s disease, multiple sclerosis, Huntington’s disease, epilepsy, and acute brain injury. This review examines the effects that emotional support dogs, dog therapy, or dog ownership has on these specific neurological disorders. It may serve as a nonpharmaceutical option to improve patient symptoms, quality of life, or the disease course itself. Articles were gathered which studied the effect of animal-assisted therapy, pet therapy, dog ownership, and physical activity on neurological disorders. Studies relating to the topic were then assessed for the impact on neurological disorders which ranged from cognition, mobility, quality of life, mood, and improvement of disease course. Dog therapy and ownership were found to improve mood, quality of life, and disease symptoms across multiple neurological disorders. It also encouraged physical activity which was shown to help many diseases studied, even ones associated with skeletal muscle apoptosis, such as Huntington’s disease. Dog therapy and ownership are a safe and effective nonpharmaceutical approach to treating chronic and progressive neurological disorders.

Activated mast cells in skeletal muscle can be a potential mediator for cancer‐associated cachexia

BackgroundEighty per cent of United States advanced cancer patients faces a worsened prognosis due to cancer‐associated cachexia. Inflammation is one driver of muscle atrophy in cachexia, and skeletal muscle‐resident immune cells could be a source of inflammation. This study explores the efficacy of cancer activated skeletal muscle‐resident mast cells as a biomarker and mediator of cachexia.MethodsIndividual gene markers for immune cells were assessed in a publicly available colon carcinoma cohort of normal (n = 3), moderate cachexia (n = 3), and severe cachexia (n = 4) mice. Lewis lung carcinoma (LL/2) cells induced cachexia in C57BL/6 mice, and a combination of toluidine blue staining, immunofluorescence, quantitative polymerase chain reaction, and western blots measured innate immune cell expression in hind limb muscles. In vitro measurements included C2C12 myotube diameter before and after treatment with media from primary murine mast cells activated with LL/2 conditioned media. To assess translational potential in human samples, innate immune cell signatures were assessed for correlation with skeletal muscle atrophy and apoptosis, dietary excess, and cachexia signatures in normal skeletal muscle tissue. Gene set enrichment analysis was performed with innate immune cell signatures in publicly available cohorts for upper gastrointestinal (GI) cancer and pancreatic ductal adenocarcinoma (PDAC) patients (accession: GSE34111 and GSE130563, respectively).ResultsIndividual innate immunity genes (TPSAB1 and CD68) showed significant increases in severe cachexia (weight loss > 15%) mice in a C26 cohort (GSE24112). Induction of cachexia in C57BL/6 mice with LL/2 subcutaneous injection significantly increased the number of activated skeletal muscle‐resident degranulating mast cells. Murine mast cells activated with LL/2 conditioned media decreased C2C12 myotube diameter (P ≤ 0.05). Normal human skeletal muscle showed significant positive correlations between innate immune cell signatures and muscle apoptosis and atrophy, dietary excess, and cachexia signatures. The mast cell signature was up‐regulated (positive normalized enrichment score and false discovery rate ≤ 0.1) in upper GI cachectic patients (n = 12) compared with control (n = 6), as well as in cachectic PDAC patients (n = 17) compared with control patients (n = 16).ConclusionsActivated skeletal muscle‐resident mast cells are enriched in cachectic muscles, suggesting skeletal‐muscle resident mast cells may serve as a biomarker and mediator for cachexia development to improve patient diagnosis and prognosis.

Lifelong Exercise in Age Rats Improves Skeletal Muscle Function and MicroRNA Profile.

Lifelong exercise is known to attenuate sarcopenia (age-associated reduction in muscle mass and function); however, the underlying molecular mechanisms remain unclear. As microRNAs are widely involved in the regulation of skeletal muscle growth and development, we aimed to evaluate the effects of lifelong regular exercise on age-related alterations in muscle microRNA expression profiles as well as on skeletal muscle atrophy, apoptosis, and mitochondria and autophagy dysfunction. Female 8-month-old Sprague-Dawley rats were divided into four groups; 1) 18 months of moderate-intensity continuous training (MICT) initiated at 8 months (adult-MICT, n = 12), 2) 8 months of MICT initiated at 18 months (presarcopenia-MICT, n = 12), 3) 8-month-old adult sedentary controls (adult-SED), and 4) 26-month-old aging sedentary controls (old-SED). Age skeletal muscles were then subjected to quantitative reverse transcription-polymerase chain reaction, Kyoto Encyclopedia of Genes and Genomes, immunoblotting, and miR-486 3' untranslated region luciferase reporter gene analyses. Age-related loss of miR-486 expression was improved, skeletal muscle atrophy and apoptosis were downregulated, and mitochondrial activity and autophagy were upregulated in the adult-MICT group. Kyoto Encyclopedia of Genes and Genomes analysis revealed that the PI3K/Akt pathway was upregulated in adult-MICT rats compared with that in old-SED. In vitro analyses in rat skeletal muscle L6 cells further confirmed that miR-486 targets PTEN, not SAV1, thereby activating the PI3K/Akt pathway and indirectly inhibiting HIPPO signaling. Compared with presarcopenia-MICT rats, adult-MICT rats experienced greater beneficial effects regarding ameliorated age-related alterations in muscle miRNA expression profile, skeletal muscle atrophy, apoptosis, and mitochondria and autophagy dysfunction, which is potentially associated with the increased miR-486 expression and concomitant targeting of the PTEN/Akt signaling pathway.

운동이 골격근에서 Bcl-2, Bax 발현비율과 세포고사에 미치는 영향

이 연구는 실험용 쥐를 대상으로 운동이 골격근에서 Bcl-2와 Bax 발현비율과 세포고사에 어떠한 영향을 미치는지에 대해 알아보고자 한 연구이다. 이를 위해 ICR계 수컷 흰쥐 20마리를 일주일의 적응기간을 거쳐 통제집단(CON : n=10)과 운동집단(AEG : n=10)으로 배정하였다. 운동은 8주간 주5회 실시하였고, 중정도 운동강도인 16.4m/min(최대산소섭취량의 65～70%)의 속도와 트레드밀 경사도 4%로 설정하여 40분간 지속적인 운동을 실시하였다. 세포고사에 대한 검증 결과 Bcl-2 단백질의 발현은 운동집단이 통제집단보다 유의하게 낮은 것으로 나타났고(p .01), Bax 단백질의 발현은 운동집단이 통제집단보다 낮게 나타났으며, Bax/Bcl-2비율은 운동집단이 통제집단보다 높게 나타났다. 따라서 규칙적 중강도 유산소운동은 세포손실을 예방 하고 운동을 통해 개선 할 수 있을 것으로 사료된다.

MicroRNA-27b-3p Targets the Myostatin Gene to Regulate Myoblast Proliferation and Is Involved in Myoblast Differentiation.

microRNAs play an important role in the growth and development of chicken embryos, including the regulation of skeletal muscle genesis, myoblast proliferation, differentiation, and apoptosis. Our previous RNA-seq studies showed that microRNA-27b-3p (miR-27b-3p) might play an important role in regulating the proliferation and differentiation of chicken primary myoblasts (CPMs). However, the mechanism of miR-27b-3p regulating the proliferation and differentiation of CPMs is still unclear. In this study, the results showed that miR-27b-3p significantly promoted the proliferation of CPMs and inhibited the differentiation of CPMs. Then, myostatin (MSTN) was confirmed to be the target gene of miR-27b-3p by double luciferase reporter assay, RT-qPCR, and Western blot. By overexpressing and interfering with MSTN expression in CPMs, the results showed that overexpression of MSTN significantly inhibited the proliferation and differentiation of CPMs. In contrast, interference of MSTN expression had the opposite effect. This study showed that miR-27b-3p could promote the proliferation of CPMs by targeting MSTN. Interestingly, both miR-27b-3p and MSTN can inhibit the differentiation of CPMs. These results provide a theoretical basis for further understanding the function of miR-27b-3p in chicken and revealing its regulation mechanism on chicken muscle growth.