Gromwell (Lithospermum erythrorhizon) Attenuates High-Fat-Induced Skeletal Muscle Wasting by Increasing Protein Synthesis and Mitochondrial Biogenesis.

Gromwell (Lithospermum erythrorhizon, LE) can mitigate obesity-induced skeletal muscle atrophy in C2C12 myotubes and high-fat diet (HFD)-induced obese mice. The purpose of this study was to investigate the anti-skeletal muscle atrophy effects of LE and the underlying molecular mechanism. C2C12 myotubes were pretreated with LE or shikonin, and active component of LE, for 24 h and then treated with 500 µM palmitic acid (PA) for an additional 24 h. Additionally, mice were fed a HFD for 8 weeks to induced obesity, and then fed either the same diet or a version containing 0.25% LE for 10 weeks. LE attenuated PA-induced myotubes atrophy in differentiated C2C12 myotubes. The supplementation of LE to obese mice significantly increased skeletal muscle weight, lean body mass, muscle strength, and exercise performance compared with those in the HFD group. LE supplementation not only suppressed obesity-induced skeletal muscle lipid accumulation, but also downregulated TNF-α and atrophic genes. LE increased protein synthesis in the skeletal muscle via the mTOR pathway. We observed LE induced increase of mitochondrial biogenesis and upregulation of oxidative phosphorylation related genes in the skeletal muscles. Furthermore, LE increased the expression of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha and the phosphorylation of adenosine monophosphate-activated protein kinase. Collectively, LE may be useful in ameliorating the detrimental effects of obesity-induced skeletal muscle atrophy through the increase of protein synthesis and mitochondrial biogenesis of skeletal muscle.

Gromwell ameliorates glucocorticoid-induced muscle atrophy through the regulation of Akt/mTOR pathway.

BACKGROUND: Muscle atrophy is characterized by decreased muscle mass, function, and strength. Synthetic glucocorticoids, including dexamethasone (Dexa), are commonly used to treat autoimmune diseases. However, prolonged exposure of Dexa with high dose exerts severe side effects, including muscle atrophy. The purpose of this study was to investigate whether Gromwell root extract (GW) can prevent Dexa-induced muscle atrophy in C2C12 cells and mice and to characterize the composition of GW to identify bioactive compounds. METHODS: For in vitro experiments, GW (0.5 and 1 µg/mL) or lithospermic acid (LA, 5 and 10 µM) was added to C2C12 myotubes on day 4 of differentiation and incubated for 24 h, along with 50 µM Dexa. For in vivo experiment, four-week-old male C57BL/6 mice were randomly divided into the four following groups (n = 7/group): Con group, Dexa group, GW0.1 group, and GW0.2 group. Mice were fed experimental diets of AIN-93 M with or without 0.1 or 0.2% GW for 4 weeks. Subsequently, muscle atrophy was induced by administering an intraperitoneal injection of Dexa at a dose of 15 mg/kg/day for 38 days, in conjunction with dietary intake. RESULTS: In Dexa-induced myotube atrophy, treatment with GW increased myotube diameter, reduced the expression of muscle atrophy markers, and enhanced the expression of myosin heavy chain (MHC) isoforms in C2C12 cells. Supplementation with the GW improved muscle function and performance in mice with Dexa-induced muscle atrophy, evidenced in the grip strength and running tests. The GW group showed increased lean body mass, skeletal muscle mass, size, and myosin heavy chain isoform expression, along with reduced skeletal muscle atrophy markers in Dexa-injected mice. Supplementation with GW increased protein synthesis and decreased protein degradation through the Akt/mammalian target of rapamycin and glucocorticoid receptor/forkhead box O3 signaling pathways, respectively. We identified LA as a potential bioactive component of the GW. LA treatment increased myotube diameter and decreased the expression of muscle atrophy markers in Dexa-induced C2C12 cells. CONCLUSIONS: These findings underscore the potential of the GW in preventing Dexa-induced skeletal muscle atrophy and highlight the contribution of LA to its effects.

Fuzhuan brick tea extract ameliorates obesity-induced skeletal muscle atrophy by alleviating mitochondrial dysfunction in mice.

Fuzhuan brick tea (FBT) is a post-fermented tea fermented by the fungus Eurotium cristatum and is mainly produced in Hunan Province, China. Our previous study revealed that FBT extract prevents obesity by increasing energy expenditure and mitochondrial content in mice. Therefore, in this study, we hypothesized that FBT extract could be effective in alleviating obesity-induced muscle atrophy by addressing mitochondrial dysfunction, and aimed to explore the underlying molecular mechanism of FBT extract in high-fat diet-induced obese mice. FBT extract increased skeletal muscle weight and size, myosin heavy chain isoforms, and muscle performance in obese mice. Additionally, FBT extract reduced obesity-induced intramuscular lipids, skeletal muscle inflammation, and the expression of skeletal muscle atrophy markers, and increased the expression of fibronectin type III domain-containing protein 5 in skeletal muscles. Obesity-induced skeletal muscle mitochondrial dysfunction was improved by FBT extract as analyzed through mitochondrial morphology, fatty acid oxidation, respiratory chain complexes, and mitochondrial dynamics and biogenesis. Epigallocatechin, a major bioactive compound in FBT extract, attenuated palmitic acid-induced muscle atrophy by regulating mitochondrial functions in C2C12 cells. In conclusion, FBT extract may prevent obesity-induced muscle atrophy by alleviating mitochondrial dysfunction in mice.

Induction of Fatty Acid Oxidation Underlies DNA Damage-Induced Cell Death and Ameliorates Obesity-Driven Chemoresistance.

The DNA damage response is essential for preserving genome integrity and eliminating damaged cells. Although cellular metabolism plays a central role in cell fate decision between proliferation, survival, or death, the metabolic response to DNA damage remains largely obscure. Here, this work shows that DNA damage induces fatty acid oxidation (FAO), which is required for DNA damage-induced cell death. Mechanistically, FAO induction increases cellular acetyl-CoA levels and promotes N-alpha-acetylation of caspase-2, leading to cell death. Whereas chemotherapy increases FAO related genes through peroxisome proliferator-activated receptor α (PPARα), accelerated hypoxia-inducible factor-1α stabilization by tumor cells in obese mice impedes the upregulation of FAO, which contributes to its chemoresistance. Finally, this work finds that improving FAO by PPARα activation ameliorates obesity-driven chemoresistance and enhances the outcomes of chemotherapy in obese mice. These findings reveal the shift toward FAO induction is an important metabolic response to DNA damage and may provide effective therapeutic strategies for cancer patients with obesity.

Long-term outcome of the endoscopic submucosal dissection of early gastric cancer: A comparison between patients with and without liver cirrhosis.

Gastric cancer (GC) and liver cirrhosis (LC) have high incidence rates, particularly in Eastern Asia; however, the long-term clinical outcomes or recurrence of GC following endoscopic submucosal dissection (ESD) in patients with comorbid LC remain unclear. The present study aimed to compare the long-term efficacy and safety of ESD in patients with GC, with and without LC. Patients with early GC (EGC) who had underlying LC and underwent endoscopic treatment (LC-EGC group) were enrolled in the present study. In addition, patients with EGC without LC (non-LC-EGC group) were matched at a ratio of 1:3 via propensity score matching. The clinical outcomes and histopathological data of both groups were analyzed. No significant differences were observed in procedure type, complications [intraprocedural bleeding (11.8%) and perforation (0.0%)], en bloc resection rate (94.1%) and complete resection rate (100%) between the two groups. Multivariate Cox regression analysis demonstrated that procedure time was significantly associated with procedure-associated bleeding [adjusted hazard ratio (HR), 1.017; 95% confidence interval (CI), 1.001-1.032; P=0.033]. Furthermore, LC was significantly associated with cancer recurrence (adjusted HR, 5.482; 95% CI, 1.102-27.279; P=0.038). Taken together, the results of the present study suggest that endoscopic resection of EGC in patients with LC is an effective and safe treatment method. However, further studies are required to assess recurrence.

Fruit of Schisandra chinensis and its bioactive component schizandrin B ameliorate obesity-induced skeletal muscle atrophy.

Schisandra chinensis fruit (Omiza in Korean), used for the production tea or liquor, and is known to enhance skeletal muscle function. However, the effect of Omiza extract (OM) on obesity-induced skeletal muscle atrophy remains unclear. This study investigated the effect of OM on skeletal muscle mass and performance in obese mice. OM increased skeletal muscle weight, size and improved skeletal muscle performance. Further, it also suppressed obesity-induced increases in proinflammatory cytokines, MuRF1, and Atrogin1 in mouse skeletal muscle and enhanced the expression of MHC and the phosphorylation of AKT/mTOR signaling molecules, thereby suppressing myostatin expression and regulating Smad-FOXO signaling. Schizandrin B, a major component of OM inhibited palmitic acid induced atrophy in C2C12 cells via Smad-FOXO regulation, suggesting that it partially contributed to the effects of OM against obesity-induced muscle atrophy. Taken together, OM may have the potential to prevent and treat obesity-induced muscle atrophy.

Fuzhuan brick tea extract prevents diet-induced obesity via stimulation of fat browning in mice.

Fuzhuan brick tea is a post-fermented tea that is intentionally fermented by the fungus Eurotium cristatum. Previous studies have reported the anti-obesity effect of Fuzhuan brick tea extracts (FBT), but the underlying mechanism remains unclear. The present study investigated whether FBT exerts anti-obesity effects through energy expenditure and browning of white adipose tissue. Mice were administered 100 mg or 200 mg FBT/kg body weight along with a high-fat diet (HFD) for 12 weeks; the FBT group had a significantly reduced body weight and adipose tissue mass compared to mice fed an HFD alone. FBT also improved serum biochemical parameters and hepatic steatosis concomitant with obesity. Furthermore, FBT enhanced energy expenditure and promoted browning of subcutaneous adipose tissue by upregulating the expression of brown adipocyte-specific genes, including uncoupling protein 1. Based on these results, we suggest that FBT induces energy expenditure by promoting the browning of subcutaneous adipose tissue, which prevents weight gain.

Predictors of Positive Video Capsule Endoscopy Findings for Chronic Unexplained Abdominal Pain: Single-Center Retrospective Study and Meta-Analysis.

Video capsule endoscopy (VCE) is an effective diagnostic modality for detecting small bowel lesions. However, the value of VCE for patients with chronic recurrent abdominal pain (CAP) of unknown etiology remains obscure. We retrospectively analyzed factors that could predict enteropathy based on the medical records of 65 patients with unexplained chronic recurrent abdominal pain (CAP) who were assessed using VCE between 2001 and 2021. We also conducted a systematic review and meta-analysis of the literature to validate our results. The positive findings of 27 (41.5%) of the 65 patients were mostly ulcerative lesions including stricture (n = 14, 60.9%) and erosion (n = 8, 29.7%). Multivariate analysis identified elevated ESR (OR, 1.06, 95% CI, 1.02-1.1, p = 0.004) as a significant risk factor for enteropathy predicted by VCE. Three eligible studies in the meta-analysis included 523 patients with CAP. Elevated C-reactive protein (CRP) (OR, 14.09; 95% CI, 2.81-70.60; p = 0.001) and erythrocyte sedimentation rate (ESR) (OR, 14.45; 95% CI, 0.92-227.33; p = 0.06) indicated VCE-positive findings in patients with unexplained abdominal pain. Elevated levels of the inflammatory markers ESR and CRP can thus predict positive VCE findings in patients with CAP.

2,6-Dimethoxy-1,4-benzoquinone increases skeletal muscle mass and performance by regulating AKT/mTOR signaling and mitochondrial function.

BACKGROUND: 2,6-Dimethoxy-1,4-benzoquinone (DMBQ), a natural phytochemical present in fermented wheat germ, has been reported to exert anti-cancer, anti-inflammatory, and anti-adipogenic effects. However, the effect of DMBQ on muscle hypertrophy and myoblast differentiation has not been elucidated. PURPOSE: We investigated the effect of DMBQ on skeletal muscle mass and muscle function and then determined the possible mechanism of DMBQ. METHODS: To examine myogenic differentiation and hypertrophy, confluent C2C12 cells were incubated in differentiation medium with or without various concentrations of DMBQ for 4 days. In animal experiments, C57BL/6 mice were fed DMBQ-containing AIN-93 diet for 7 weeks. Grip strength, treadmill, microscopic evaluation of muscle tissue, western blotting, and quantitative real-time PCR were performed. RESULTS: DMBQ significantly increased fusion index, myotube size, and the protein expression of myosin heavy chain (MHC). DMBQ increased the phosphorylation of protein kinase B (AKT) and p70 ribosomal protein S6 kinase (S6K), whereas the phosphorylation of these proteins was abolished by the phosphoinositide 3-kinase inhibitor LY294002 in C2C12 cells. In addition, DMBQ treatment increased peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α), which programs mitochondrial biogenesis, protein levels compared with control C2C12 cells. DMBQ significantly increased maximal respiration and spare respiratory capacity in C2C12 cells. In animal experiments, DMBQ increased skeletal muscle weights and skeletal muscle fiber size compared with the control group values. In addition, the DMBQ group showed increased grip strength and running distance on an accelerating treadmill. The protein expression of total MHC, MHC1, MHC2A, and MHC2B in skeletal muscle was upregulated by DMBQ supplementation. We found that DMBQ increased the phosphorylation of AKT and mammalian target of rapamycin (mTOR), as well as downstream S6K and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) in skeletal muscle. DMBQ also stimulated mRNA expression of PGC1α, accompanied by an increase in mitochondrial DNA content, oxidative phosphorylation (OXPHOS) proteins, and oxidative enzyme activity. CONCLUSION: Collectively, DMBQ was shown to increase skeletal muscle mass and performance by regulating the AKT/mTOR signaling pathway and enhancing mitochondrial function, which might be useful for the treatment and prevention of skeletal muscle atrophy.

Identifying Codium fragile extract components and their effects on muscle weight and exercise endurance.

Codium fragile (CF) is a type of green algae consumed as kimchi in Asia. UPLC-QTOF-MS/MS analysis showed that CF contain lysophosphatidyl choline, canthaxanthin, retinoic acid, α-tocopherol, and unsaturated fatty acids, which reportedly improve skeletal muscle health. However, the effect of CF on skeletal muscle mass and function remains to be elucidated. In mice fed with CF extracts, exercise endurance and muscle weight increased. CF extracts enhanced protein synthesis and myogenic differentiation through the mTORC1 pathway. CF extracts also promoted oxidative muscle fiber formation and mitochondrial biogenesis through the PGC-1α-related signaling pathway. Upregulation of PGC-1α by CF extracts was abolished by EX527 SIRT1 inhibitor treatment. Changed signaling molecules in the CF extracts were partially regulated by canthaxanthin, a new compound in CF extracts, suggesting that canthaxanthin contribute synergistically to the effect of CF extracts. Therefore, CF is a potential food source for sport nutrition or prevention of sarcopenia.

Chrysanthemi Zawadskii var. Latilobum Attenuates Obesity-Induced Skeletal Muscle Atrophy via Regulation of PRMTs in Skeletal Muscle of Mice.

As obesity promotes ectopic fat accumulation in skeletal muscle, resulting in impaired skeletal muscle and mitochondria function, it is associated with skeletal muscle loss and dysfunction. This study investigated whether Chrysanthemi zawadskii var. latilobum (CZH) protected mice against obesity-induced skeletal muscle atrophy and the underlying molecular mechanisms. High-fat diet (HFD)-induced obese mice were orally administered either distilled water, low-dose CZH (125 mg/kg), or high-dose CZH (250 mg/kg) for 8 w. CZH reduced obesity-induced increases in inflammatory cytokines levels and skeletal muscle atrophy, which is induced by expression of atrophic genes such as muscle RING-finger protein 1 and muscle atrophy F-box. CZH also improved muscle function according to treadmill running results and increased the muscle fiber size in skeletal muscle. Furthermore, CZH upregulated mRNA and protein levels of protein arginine methyltransferases (PRMT)1 and PRMT7, which subsequently attenuated mitochondrial dysfunction in the skeletal muscle of obese mice. We also observed that CZH significantly decreased PRMT6 mRNA and protein expression, which resulted in decreased muscle atrophy. These results suggest that CZH ameliorated obesity-induced skeletal muscle atrophy in mice via regulation of PRMTs in skeletal muscle.

Scopolin ameliorates high-fat diet induced hepatic steatosis in mice: potential involvement of SIRT1-mediated signaling cascades in the liver.

The present study aimed to investigate whether scopolin exhibits beneficial effects on high-fat diet (HFD)-induced hepatic steatosis in mice. The involvement of sirtuin 1 (SIRT1) as a molecular target for scopolin was also explored. Scopolin decreased the Km of SIRT1 for p53 and nicotinamide adenine dinucleotide without altering Vmax in a cell-free system. Scopolin alleviated oleic acid-induced lipid accumulation and downregulation of SIRT1 activity in HepG2 cells, and these beneficial effects of scopolin were abolished in the presence of SIRT1 inhibitor. Mice administered 0.02% scopolin for 8 weeks exhibited improved phenotypes of HFD-induced hepatic steatosis along with increased hepatic SIRT1 activity and protein expression. Scopolin resulted in increased deacetylation of sterol regulatory element-binding protein 1c with subsequent downregulation of lipogenic genes, and enhanced deacetylation of protein peroxisome proliferator-activated receptor-γ coactivator 1α with upregulation of fatty acid oxidation genes in livers. Scopolin also enhanced deacetylation of nuclear factor-kappa enhancer binding protein and liver kinase B1 (LKB1), facilitating LKB1/AMP-activated protein kinase signaling cascades. Scopolin attenuated hepatic steatosis through activation of SIRT1-mediated signaling cascades, a potent regulator of lipid homeostasis. Increased hepatic SIRT1 activity and protein expression appeared to be associated with these beneficial effects of scopolin.