Search Results (16)

Background: ETAS^®, a standardized extract of Asparagus officinalis stem, has been found to alleviate cognitive impairment in senescence-accelerated mice prone 8 (SAMP8) and is now considered a functional food in aging. The present study aimed to investigate the impacts of ETAS^® on relieving aging-related muscle atrophy in SAMP8 mice. Methods: The SAMP8 mice were fed a regular diet supplemented with 200 or 1000 mg/kg BW ETAS^®50 for 12 weeks. Grip strength, muscle mass, and molecular markers of protein synthesis, degradation, and mitochondrial quality were assessed. Results: We found that ETAS^® significantly increased grip strength and muscle mass in SAMP8 mice. At the molecular level, ETAS^® significantly upregulated protein synthesis via PI3K/Akt/mTOR/p70S6K and downregulated protein degradation via FoxO1a/atrogin-1 and MuRF-1 and myostatin via NFκB expression. In addition, ETAS^® improved mitochondrial quality via promoting mitochondrial biogenesis genes, oxidative respiration genes, fusion/fission genes, PGC1α, and PINK1 proteins and maintained the autophagic flux via reducing ATG13, LC3-II/LC3-I, and p62. Conclusions: ETAS^® exerts beneficial effects on sarcopenia by modulating the positive protein turnover and improving mitochondrial quality in aging. Full article

Diabetic muscular atrophy is a complication of diabetes mellitus that can decrease quality of life. Its complex mechanisms include alterations in proteolytic pathways, oxidative stress, and intracellular lipid accumulation. NADPH oxidase enzymes (NOX) play a key role in the production of ROS, contributing to oxidative damage and insulin resistance. Apocynin, a NOX inhibitor, has antioxidant and anti-inflammatory effects, suggesting its therapeutic potential in various diabetic complications. This study evaluated the impact of apocynin on the mechanisms of muscle atrophy in slow- and fast-twitch muscles of diabetic rats. Diabetes was induced in male Wistar rats by intraperitoneal injection of a single dose of streptozotocin (60 mg/kg). Apocynin treatment (3 mg/kg/day) was administered for 8 weeks. Fasting blood glucose levels, lipid profile, and weight gain were measured. Both slow-twitch (soleus) and fast-twitch (extensor digitorum longus, EDL) skeletal muscles were weighed and used to assess triglycerides (TG) content, histological analysis, lipid peroxidation levels, and gene expression evaluated by qRT-PCR. Apocynin reduced blood glucose levels, improved body weight, and exhibited hypolipidemic effects. It significantly increased muscle weight in EDL and soleus, especially in EDL muscle, lowering triglycerides, lipid peroxidation, and increasing fiber size. Additionally, it decreased mRNA expression levels of MuRF-1, atrogin-1, myostatin and p47phox mRNA and upregulated PGC-1α and follistatin mRNA. Apocynin exerted a myoprotective effect by mitigating muscle atrophy in diabetic rats. Its effects were differentially mediated on TG accumulation and muscle fiber size, reducing oxidative stress, atrogene expression, and positively regulating PGC-1α. Full article

This study investigated the effects of dietary carbohydrate levels (control 8.13%, HG1 12.03%, and HG2 14.15%) on growth performance and glutamate metabolism in Chinese perch (S. chuatsi) (initial weight: 39.12 ± 0.25 g) reared at 12–15 °C. Diets were isonitrogenous (49% protein). After 8 weeks, the HG1 group optimized weight gain rate (WGR), specific growth rate (SGR), and protein efficiency ratio (PER), while reducing feed conversion ratio (FCR). HG1 and HG2 groups reduced liver glutamate/glutamine levels while downregulating the expression of key ammonia-metabolizing genes (gs, gdh, and ampd), collectively suppressing glutamate-mediated ammonia excretion. HG1 and HG2 groups enhanced glycolysis (upregulated gk and pk) coupled with suppressed gluconeogenesis (decreased PEPCK and G6Pase activities) in the liver. Concurrent downregulation of proteolytic markers (mafbx and murf1) in the muscle indicated improved protein conservation efficiency in the HG1 and HG2 groups. The HG1 diet optimally enhances growth by promoting glycolysis, reducing ammonia excretion, and improving feed efficiency. The insights gained from this research will be used to refine the low-temperature culture feed for Chinese perch, aiming to decrease ammonia and nitrogen emissions, thereby advancing the practice of low-ammonia emission culture for this species. Full article

Sarcopenia, a serious consequence of chronic kidney disease (CKD), is driven by elevated myostatin (MSTN), a key inhibitor of muscle growth. This study explored the potential of an MSTN-specific antisense oligonucleotide (ASO) in reversing CKD-induced muscle wasting in a mouse model. Thirty-two male C57BL/6J mice were randomly assigned to a non-CKD group (n = 8, regular diet) and a CKD group (n = 24, adenine diet). CKD was induced using a 0.2% adenine-supplemented diet for 4 weeks. Following this, the mice were sub-grouped into CKD (saline, n = 8), CKD + Low-Dose ASO (25 mg/kg ASO, n = 8), and CKD + High-Dose ASO (50 mg/kg ASO, n = 8). ASO was administered via subcutaneous injections for 8 weeks. Muscle mass, treadmill performance, grip strength, and muscle fiber morphology were assessed alongside qPCR and Western blot analysis for MSTN, atrogin-1, and MuRF-1 expression. ASO therapy significantly enhanced muscle mass and function and enlarged muscle fibers while effectively downregulating muscle degradation markers. These improvements occurred without compromising renal function, as confirmed by BUN, creatinine, kidney weight, and histological analysis. This study is the first to demonstrate the efficacy of ASO therapy in mitigating CKD-induced sarcopenia, offering a promising targeted gene therapy with significant clinical implications for improving nutritional status and physical performance in CKD. Full article

This study evaluated changes over time in skeletal muscle atrophy, expressions of skeletal muscle anabolic and catabolic genes, and mitochondrial activity by skeletal muscle type in an adenine-induced chronic kidney disease (CKD) model. A CKD model was successfully established by feeding male Wistar rats a 0.75% adenine diet for 4 weeks starting at 8 weeks of age. Control and CKD groups were sacrificed at 12 and 20 weeks of age. The back muscles were analyzed histologically, and succinate dehydrogenase (SDH) staining was performed to evaluate mitochondrial activity. Gene expressions of myogenic determination gene number 1 and myogenin as indicators of muscle anabolism, atrogin-1 and muscle RING-finger protein-1 (MuRF1) as indicators of muscle catabolism, and peroxisome proliferator-activated receptor-γ coactivator-1-α as a marker of mitochondrial biogenesis were assessed. Type I and type II muscle cross-sectional areas (CSAs) were decreased at 12 weeks, but type I muscle CSA was recovered at 20 weeks. SDH staining was lower in CKD than in control rats at 12 weeks, but no significant difference was observed at 20 weeks. Increased expressions of myogenin, atrogin-1, and MuRF-1 were observed only at 12 weeks, but no differences were observed at 20 weeks. The adenine-induced CKD rat model appears to show changes in muscle atrophy over time. Full article

The prevalence of skeletal muscle atrophy, caused by disease and aging, is rising as life expectancy increases. Exercise is the most effective treatment option; however, it is often impractical for individuals suffering from disease or bedridden. The formulation of non-exercise-based interventions is necessary. This study assessed the impact of acupuncture (AC), electro-acupuncture (EA), and electrical stimulation (ES) on muscle mass and contractile properties in a model of casting-induced muscle atrophy. Sprague-Dawley rats (n = 40) were assigned to five groups: control (CON), cast (CT), cast receiving AC (CT-AC), cast receiving EA (CT-EA), and cast receiving ES (CT-ES) (n = 8 each). Treatments were 15 min and three times/week for 14 days. Contractile properties and protein markers of atrophy and inflammation were measured. Casting decreased muscle mass and fiber cross-sectional area, but AC, EA, and ES attenuated cast-induced muscle atrophy. All treatments increased peak twitch tension compared to CT. CT increased the protein levels of MAFbx and MuRF1, while AC, EA, and ES mitigated the elevation of these proteins. Our results indicate that acupuncture, electro-acupuncture, and electrical stimulation show promise as therapeutic strategies to counteract skeletal muscle loss and dysfunction resulting from disuse atrophy caused by injury, disease, and aging. Full article

Sarcopenia refers to an age-related decrease in muscle mass and strength. The gut–muscle axis has been proposed as a promising target to alleviate muscle atrophy. The effect of KL-Biome—a postbiotic preparation comprising heat-killed Lactiplantibacillus plantarum KM-2, its metabolites, and an excipient (soybean powder)—on muscle atrophy was evaluated using dexamethasone (DEX)-induced atrophic C2C12 myoblasts and C57BL/6J mice. KL-Biome significantly downregulated the expression of genes (Atrogin-1 and MuRF1) associated with skeletal muscle degradation but increased the anabolic phosphorylation of FoxO3a, Akt, and mTOR in C2C12 cells. Oral administration of KL-Biome (900 mg/kg) for 8 weeks significantly improved muscle mass, muscle function, and serum lactate dehydrogenase levels in DEX-treated mice. KL-Biome administration increased gut microbiome diversity and reversed DEX-mediated gut microbiota alterations. Furthermore, it significantly increased the relative abundances of the genera Subdologranulum, Alistipes, and Faecalibacterium prausnitzii, which are substantially involved in short-chain fatty acid production. These findings suggest that KL-Biome exerts beneficial effects on muscle atrophy by regulating gut microbiota. Full article

Heart failure with preserved ejection fraction (HFpEF) is associated with exercise intolerance due to alterations in the skeletal muscle (SKM). Leucine supplementation is known to alter the anabolic/catabolic balance and to improve mitochondrial function. Thus, we investigated the effect of leucine supplementation in both a primary and a secondary prevention approach on SKM function and factors modulating muscle function in an established HFpEF rat model. Female ZSF1 obese rats were randomized to an untreated, a primary prevention, and a secondary prevention group. For primary prevention, leucine supplementation was started before the onset of HFpEF (8 weeks of age) and for secondary prevention, leucine supplementation was started after the onset of HFpEF (20 weeks of age). SKM function was assessed at an age of 32 weeks, and SKM tissue was collected for the assessment of mitochondrial function and histological and molecular analyses. Leucine supplementation prevented the development of SKM dysfunction whereas it could not reverse it. In the primary prevention group, mitochondrial function improved and higher expressions of mitofilin, Mfn-2, Fis1, and miCK were evident in SKM. The expression of UCP3 was reduced whereas the mitochondrial content and markers for catabolism (MuRF1, MAFBx), muscle cross-sectional area, and SKM mass did not change. Our data show that leucine supplementation prevented the development of skeletal muscle dysfunction in a rat model of HFpEF, which may be mediated by improving mitochondrial function through modulating energy transfer. Full article

Necroptosis, an actively researched form of programmed cell death closely related to the inflammatory response, is important in a variety of disorders and diseases. However, the relationship between necroptosis and muscle protein degradation in cachexia is rarely reported. This study aimed to elucidate whether necroptosis played a crucial role in muscle protein degradation in a cachexia model of weaned piglets induced by lipopolysaccharide (LPS). In Experiment 1, the piglets were intraperitoneally injected with LPS to construct the cachexia model, and sacrificed at different time points after LPS injection (1, 2, 4, 8, 12, and 24 h). In Experiment 2, necrostatin-1 (Nec-1), a necroptosis blocker, was pretreated in piglets before the injection of LPS to inhibit the occurrence of necroptosis. Blood and longissimus dorsi muscle samples were collected for further analysis. In the piglet model with LPS-induced cachexia, the morphological and ultrastructural damage, and the release of pro-inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were dynamically elicited in longissimus dorsi muscle. Further, protein concentration and protein/DNA ratio were dynamically decreased, and protein degradation signaling pathway, containing serine/threonine kinase (Akt), Forkhead box O (FOXO), muscular atrophy F-box (MAFbx), and muscle ring finger protein 1 (MuRF1), was dynamically activated in piglets after LPS challenge. Moreover, mRNA and protein expression of necroptosis signals including receptor-interacting protein kinase (RIP)1, RIP3, and mixed lineage kinase domain-like pseudokinase (MLKL), were time-independently upregulated. Subsequently, when Nec-1 was used to inhibit necroptosis, the morphological damage, the increase in expression of pro-inflammatory cytokines, the reduction in protein content and protein/DNA ratio, and the activation of the protein degradation signaling pathway were alleviated. These results provide the first evidence that necroptosis mediates muscle protein degradation in cachexia by LPS challenge. Full article

Muscle atrophy is one of the main causes of sarcopenia—the age-related loss of skeletal muscle. In this study, we investigated the effect of turmeric (Curcuma longa) extract (TE) supplementation on age-related muscle atrophy in a senescence-accelerated mouse model and explored the underlying mechanisms. Twenty-six-week-old male, senescence-accelerated mouse resistant (SAMR) mice received the AIN-93G basal diet, while twenty-six-week-old male, senescence-accelerated mouse prone 8 (SAMP8) mice received the AIN-93G basal diet or a 2% TE powder-supplemented diet for ten weeks. Our findings revealed that TE supplementation showed certain effects on ameliorating the decrease in body weight, tibialis anterior weight, and mesenteric fat tissue weight in SAMP8 mice. TE improved gene expression in the glucocorticoid receptor-FoxO signaling pathway in skeletal muscle, including redd1, klf15, foxo1, murf1, and mafbx. Furthermore, TE might have the certain potential on improving the dynamic balance between anabolic and catabolic processes by inhibiting the binding of glucocorticoid receptor or FoxO1 to the glucocorticoid response element or FoxO-binding element in the MuRF1 promoter in skeletal muscle, thereby promoting muscle mass and strength, and preventing muscle atrophy and sarcopenia prevention. Moreover, TE may have reduced mitochondrial damage and maintained cell growth and division by downregulating the mRNA expression of the genes mfn2 and tsc2. Thus, the results indicated TE’s potential for preventing age-related muscle atrophy and sarcopenia. Full article

Cancer cachexia describes a syndrome of muscle wasting and lipolysis that is still largely untreatable and negatively impacts prognosis, mobility, and healthcare costs. Since upregulation of skeletal muscle monoamine-oxidase-A (MAO-A), a source of reactive oxygen species, may contribute to cachexia, we investigated the effects of the MAO-inhibitor harmine-hydrochloride (HH, intraperitoneal, 8 weeks) on muscle wasting in a triple-transgenic mouse model of pancreatic ductal adenocarcinoma (PDAC) and wild type (WT) mice. Gastrocnemius and soleus muscle cryo-cross-sections were analyzed for fiber type-specific cross-sectional area (CSA), fraction and capillarization using ATPase- and lectin-stainings. Transcripts of pro-apoptotic, -atrophic, and -inflammatory signals were determined by RT-qPCR. Furthermore, we evaluated the integrity of neuromuscular junction (NMJ, pre-/post-synaptic co-staining) and mitochondrial ultrastructure (transmission electron microscopy). MAO-A expression in gastrocnemius muscle was increased with PDAC vs. WT (immunohistochemistry: p < 0.05; Western blot: by trend). PDAC expectedly reduced fiber CSA and upregulated IL-1β in both calf muscles, while MuRF1 expression increased in soleus muscle only. Although IL-1β decreased, HH caused an additional 38.65% (p < 0.001) decrease in gastrocnemius muscle (IIBX) fiber CSA. Moreover, soleus muscle CSA remained unchanged despite the downregulation of E3-ligases FBXO32 (p < 0.05) and MuRF1 (p < 0.01) through HH. Notably, HH significantly decreased the post-synaptic NMJ area (quadriceps muscle) and glutathione levels (gastrocnemius muscle), thereby increasing mitochondrial damage and centronucleation in soleus and gastrocnemius type IIBX fibers. Moreover, although pro-atrophic/-inflammatory signals are reversed, HH unfortunately fails to stop and rather promotes PDAC-related muscle wasting, possibly via denervation or mitochondrial damage. These differential adverse vs. therapeutic effects warrant studies regarding dose-dependent benefits and risks with consideration of other targets of HH, such as the dual-specificity tyrosine phosphorylation regulated kinases 1A and B (DYRK1A/B). Full article

The incidence of sarcopenic obesity gradually increased in parallel with the aged population. This research examined the effects of whey peptide (WP) supplementation with/without resistant exercise (RE) on sarcopenic obesity. Male 8-month-old C57BL/6J mice were fed a control diet (10 kcal% fat) or a high-fat diet (60 kcal% fat) for 8 weeks. High-fat diet-fed mice were randomly divided into four groups: obesity control group (OB), RE (RE only), WP (WP only), and WPE (RE and WP). WP supplementation (1500 mg/day/kg B.W.) gavage and RE (ladder climbing, five times weekly, 8–10 repetitions, 10–20% B.W. load) were conducted for an additional 8 weeks. Protein and mRNA levels of markers related to energy, protein, and lipid metabolism were analyzed in skeletal muscle and adipose tissue by one-way analysis of variance (ANOVA). WP supplementation regardless of RE significantly suppressed the increasing fat mass (p = 0.016) and decreasing lean mass (p = 0.014) and alleviated abnormal morphological changes in skeletal muscle and adipose tissue (p < 0.001). In adipose tissue, WP supplementation regardless of RE ameliorated dysregulated energy metabolism and contributed to the reduction in adipocyte differentiation (PPAR-γ (p = 0.017), C/EBPα (p = 0.034)). In skeletal muscle, WP supplementation regardless of RE alleviated energy metabolism dysregulation and resulted in down-regulated protein degradation (Atrogin-1 (p = 0.003), MuRF1 (p = 0.006)) and apoptosis (Bax) (p = 0.004). Taken together, the current study elucidated that WP supplementation regardless of RE has potential anti-obesity and anti-sarcopenic effects in sarcopenic obesity. Full article

The ubiquitin proteasome system (UPS) is the main player of skeletal muscle wasting, a common characteristic of many diseases (cancer, etc.) that negatively impacts treatment and life prognosis. Within the UPS, the E3 ligase MuRF1/TRIM63 targets for degradation several myofibrillar proteins, including the main contractile proteins alpha-actin and myosin heavy chain (MHC). We previously identified five E2 ubiquitin-conjugating enzymes interacting with MuRF1, including UBE2L3/UbcH7, that exhibited a high affinity for MuRF1 (K_D = 50 nM). Here, we report a main effect of UBE2L3 on alpha-actin and MHC degradation in catabolic C2C12 myotubes. Consistently UBE2L3 knockdown in Tibialis anterior induced hypertrophy in dexamethasone (Dex)-treated mice, whereas overexpression worsened the muscle atrophy of Dex-treated mice. Using combined interactomic approaches, we also characterized the interactions between MuRF1 and its substrates alpha-actin and MHC and found that MuRF1 preferentially binds to filamentous F-actin (K_D = 46.7 nM) over monomeric G-actin (K_D = 450 nM). By contrast with actin that did not alter MuRF1–UBE2L3 affinity, binding of MHC to MuRF1 (K_D = 8 nM) impeded UBE2L3 binding, suggesting that differential interactions prevail with MuRF1 depending on both the substrate and the E2. Our data suggest that UBE2L3 regulates contractile proteins levels and skeletal muscle atrophy. Full article

Vitamin D (VD) deficiency is associated with musculoskeletal disorders. This study examines whether co-supplementation of l-cysteine (LC) and VD is better than monotherapy with LC or VD at alleviating musculoskeletal dyshomeostasis in the skeletal muscle of VD-deficient high-fat diet (HFD-VD-) fed mice. Mice were fed a healthy diet or an HFD; for VD-deficient animals, the mice were maintained on a HFD-VD-diet (16 weeks); after the first 8 weeks, the HFD-VD-diet-fed mice were supplemented for another 8 weeks with LC, VD-alone, or the same doses of LC + VD by oral gavage. Saline and olive oil served as controls. Myotubes were exposed with high-glucose, palmitate, Monocyte Chemoattractant Protein 1 (MCP-1), and Tumor Necrosis Factor (TNF), to mimic the in vivo microenvironment. In vitro deficiencies of glutathione and hydrogen sulfide were induced by knockdown of GCLC and CSE genes. Relative gene expression of biomarkers (myogenic: MyoD, Mef2c, Csrp3; muscle dystrophy: Atrogin1, Murf1, and Myostatin; bone modeling and remodeling: RANK, RANKL, OPG) were analyzed using qRT-PCR. Co-supplementatoin with LC + VD showed beneficial effects on gene expression of myogenic markers and OPG but reduced markers of dystrophy, RANK/RANKL in comparison to LC or VD alone-supplementation. In vitro myotubes treated with glutathione (GSH) precursors also showed a positive effect on OPG and the myogenesis genes, and inhibited RANK/RANKL and muscle-dystrophy markers. This study reveals that the co-supplementation of LC with VD significantly alleviates the markers of musculoskeletal disorders in the skeletal muscle better than monotherapy with LC or VD in HFD-VD-fed mice. Full article

Drug screening systems for muscle atrophy based on the contractile force of cultured skeletal muscle tissues are required for the development of preventive or therapeutic drugs for atrophy. This study aims to develop a muscle atrophy model by inducing atrophy in normal muscle tissues constructed on microdevices capable of measuring the contractile force and to verify if this model is suitable for drug screening using the contractile force as an index. Tissue engineered skeletal muscles containing striated myotubes were prepared on the microdevices for the study. The addition of 100 µM dexamethasone (Dex), which is used as a muscle atrophy inducer, for 24 h reduced the contractile force significantly. An increase in the expression of Atrogin-1 and MuRF-1 in the tissues treated with Dex was established. A decrease in the number of striated myotubes was also observed in the tissues treated with Dex. Treatment with 8 ng/mL Insulin-like Growth Factor (IGF-I) for 24 h significantly increased the contractile force of the Dex-induced atrophic tissues. The same treatment, though, had no impact on the force of the normal tissues. Thus, it is envisaged that the atrophic skeletal muscle tissues induced by Dex can be used for drug screening against atrophy. Full article