TMUB1 is an endoplasmic reticulum-resident escortase that promotes the p97-mediated extraction of membrane proteins for degradation.

Membrane protein clients of endoplasmic reticulum (ER)-associated degradation must be retrotranslocated from the ER membrane by the AAA-ATPase p97 for proteasomal degradation. Before direct engagement with p97, client transmembrane domains (TMDs) that have partially or fully crossed the membrane must be constantly shielded to avoid non-native interactions. How client TMDs are seamlessly escorted from the membrane to p97 is unknown. Here, we identified ER-anchored TMUB1 as a TMD-specific escortase. TMUB1 interacts with the TMD of clients within the membrane and holds ∼10-14 residues of a hydrophobic sequence that is exposed out of membrane, using its transmembrane and cytosolic regions, respectively. The ubiquitin-like domain of TMUB1 recruits p97, which can pull client TMDs from bound TMUB1 into the cytosol. The disruption of TMUB1 escortase activity impairs retrotranslocation and stabilizes retrotranslocating intermediates of client proteins within the ER membrane. Thus, TMUB1 promotes TMD segregation by safeguarding the TMD movement from the membrane to p97.

RNF126-Mediated Reubiquitination Is Required for Proteasomal Degradation of p97-Extracted Membrane Proteins.

Valosin-containing protein (VCP)/p97 is an AAA-ATPase that extracts polyubiquitinated substrates from multimeric macromolecular complexes and biological membranes for proteasomal degradation. During p97-mediated extraction, the substrate is largely deubiquitinated as it is threaded through the p97 central pore. How p97-extracted substrates are targeted to the proteasome with few or no ubiquitins is unknown. Here, we report that p97-extracted membrane proteins undergo a second round of ubiquitination catalyzed by the cytosolic ubiquitin ligase RNF126. RNF126 interacts with transmembrane-domain-specific chaperone BAG6, which captures p97-liberated substrates. RNF126 depletion in cells diminishes the ubiquitination of extracted membrane proteins, slows down their turnover, and dramatically stabilizes otherwise transient intermediates in the cytosol. We reconstitute the reubiquitination of a p97-extracted, misfolded multispanning membrane protein with purified factors. Our results demonstrate that p97-extracted substrates need to rapidly engage ubiquitin ligase-chaperone pairs that rebuild the ubiquitin signal for proteasome targeting to prevent harmful accumulation of unfolded intermediates.

The transcription factor MYB110 regulates plant height, lodging resistance, and grain yield in rice.

The high-yielding Green Revolution varieties of cereal crops are characterized by a semidwarf architecture and lodging resistance. Plant height is tightly regulated by the availability of phosphate (Pi), yet the underlying mechanism remains obscure. Here, we report that rice (Oryza sativa) R2R3-type Myeloblastosis (MYB) transcription factor MYB110 is a Pi-dependent negative regulator of plant height. MYB110 is a direct target of PHOSPHATE STARVATION RESPONSE 2 (OsPHR2) and regulates OsPHR2-mediated inhibition of rice height. Inactivation of MYB110 increased culm diameter and bending resistance, leading to enhanced lodging resistance despite increased plant height. Strikingly, the grain yield of myb110 mutants was elevated under both high- and low-Pi regimes. Two divergent haplotypes based on single nucleotide polymorphisms in the putative promoter of MYB110 corresponded with its transcript levels and plant height in response to Pi availability. Thus, fine-tuning MYB110 expression may be a potent strategy for further increasing the yield of Green Revolution cereal crop varieties.

Viscosity of Ionic Liquids: Theories and Models.

Ionic liquids (ILs) offer a wide range of promising applications due to their unique and designable properties compared to conventional solvents. Further development and application of ILs require correlating/predicting their pressure-viscosity-temperature behavior. In this review, we firstly introduce methods for calculation of thermodynamic inputs of viscosity models. Next, we introduce theories, theoretical and semi-empirical models coupling various theories with EoSs or activity coefficient models, and empirical and phenomenological models for viscosity of pure ILs and IL-related mixtures. Our modelling description is followed immediately by model application and performance. Then, we propose simple predictive equations for viscosity of IL-related mixtures and systematically compare performances of the above-mentioned theories and models. In concluding remarks, we recommend robust predictive models for viscosity at atmospheric pressure as well as proper and consistent theories and models for P-η-T behavior. The work that still remains to be done to obtain the desired theories and models for viscosity of ILs and IL-related mixtures is also presented. The present review is structured from pure ILs to IL-related mixtures and aims to summarize and quantitatively discuss the recent advances in theoretical and empirical modelling of viscosity of ILs and IL-related mixtures.

Photochemical dearomative skeletal modifications of heteroaromatics.

Dearomatization has emerged as a powerful tool for rapid construction of 3D molecular architectures from simple, abundant, and planar (hetero)arenes. The field has evolved beyond simple dearomatization driven by new synthetic technology development. With the renaissance of photocatalysis and expansion of the activation mode, the last few years have witnessed impressive developments in innovative photochemical dearomatization methodologies, enabling skeletal modifications of dearomatized structures. They offer truly efficient and useful tools for facile construction of highly complex structures, which are viable for natural product synthesis and drug discovery. In this review, we aim to provide a mechanistically insightful overview on these innovations based on the degree of skeletal alteration, categorized into dearomative functionalization and skeletal editing, and to highlight their synthetic utilities.

Bright Nonblinking Photoluminescence with Blinking Lifetime from a Nanocavity-Coupled Quantum Dot.

Colloidal quantum dots (QDs) are excellent luminescent nanomaterials for many optoelectronic applications. However, photoluminescence blinking has limited their practical use. Coupling QDs to plasmonic nanostructures shows potential in suppressing blinking. However, the underlying mechanism remains unclear and debated, hampering the development of bright nonblinking dots. Here, by deterministically coupling a QD to a plasmonic nanocavity, we clarify the mechanism and demonstrate unprecedented single-QD brightness. In particular, we report for the first time that a blinking QD could obtain nonblinking photoluminescence with a blinking lifetime through coupling to the nanocavity. We show that the plasmon-enhanced radiative decay outcompetes the nonradiative Auger process, enabling similar quantum yields for charged and neutral excitons in the same dot. Meanwhile, we demonstrate a record photon detection rate of 17 MHz from a colloidal QD, indicating an experimental photon generation rate of more than 500 MHz. These findings pave the way for ultrabright nonblinking QDs, benefiting diverse QD-based applications.

General Synthesis of Composition-Tunable High-Entropy Amorphous Oxides Toward High Efficiency Oxygen Evolution Reaction.

High-entropy materials have attracted much attention in the electrocatalysis field due to their unique structure, high chemical activity, and compositional tunability. However, the harsh and complex synthetic methods limit the application of such materials. Herein, a universal non-equilibrium liquid-phase synthesis strategy is reported to prepare high-entropy amorphous oxide nanoparticles (HEAO-NPs), and the composition of HEAO-NPs can be precisely controlled from tri- to ten-component. The non-equilibrium synthesis environment provided by an excessively strong reducing agent overcomes the difference in the reduction potentials of various metal ions, resulting in the formation of HEAO-NPs with a nearly equimolar ratio. The oxygen evolution reaction (OER) performance of HEAO-NPs is further improved by adjusting the composition and optimizing the electronic structure. The Fe16Co32Ni32Mn10Cu10BOy exhibits a smaller overpotential (only 259 mV at 10 mA cm-2) and higher stability in OER compared with commercial RuO2. The amorphous high-entropy structure with an optimized concentration of iron makes the binding energy of CoNi shift to a higher direction, promotes the generation of high-valence active intermediates, and accelerates the OER kinetic process. The HEAO-NPs have promising application potential in the field of catalysis, biology, and energy storage, and this work provides a general synthesis method for composition-controllable high-entropy materials.

Selenol Switch Assay for Selenoprotein Derivatization.

Selenoproteins are a class of protein that have selenocysteine (Sec) residues, and essential for diverse cellular functions. Although the human genome encodes 25 selenoproteins, nearly half of these selenoproteins' function is not clear. This is largely due to the lack of convenient methods to study selenoproteins. We report in this work a novel Selenol Switch assay to exclusively derivatize selenoproteins. The Selenol Switch assay relies on the selective conversion of the Sec residue to the electrophilic dehydroalanine (DHA) residue, which is then labeled by nucleophiles. The multiple reactions of the Selenol Switch assay are readily performed in a single test tube, and the conversion yield is nearly quantitative. The abundance of selenoproteins in mouse tissues determined by the Selenol Switch assay is consistent with that from the classical ICP-MS assay, validating the reliability of the Selenol Switch assay in studying selenoproteins.

High-power polarization-maintaining LP11-mode fiber laser based on long-period fiber grating for precise welding.

An LP11-mode output all-fiber laser was presented, utilizing long-period fiber gratings (LPFGs) and polarization-maintaining optical fiber (PMF). The LPFG was designed and fabricated, achieving a 90.56% efficiency in LP01 to LP11 mode conversion. Furthermore, the transmission stability of LP11-mode in the PMF was also explored, with the spatial mode overlap ratio exceeding 0.95. Ultimately, the high-power polarization-maintaining (PM) fiber laser, capable of the LP11 mode output, was constructed, with the output power of 600 W and the beam quality M2 of 2.84. During the process of welding a thick Al-plate, the LP11 fiber laser exhibits a notable 1.88 times greater depth of fusion compared to the commercial single-mode fiber laser, when operating at the laser welding head speed of 100 mm/s. For applications demanding non-circular symmetric high-order modes, this research holds substantial potential for widespread adoption within the field of industrial processing.

The role of body composition in left ventricular remodeling, reverse remodeling, and clinical outcomes for heart failure with mildly reduced ejection fraction: more knowledge to the "obesity paradox".

BACKGROUND: Although the "obesity paradox" is comprehensively elucidated in heart failure (HF) with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF), the role of body composition in left ventricular (LV) remodeling, LV reverse remodeling (LVRR), and clinical outcomes is still unclear for HF with mildly reduced ejection fraction (HFmrEF). METHODS: Our study is a single-centre, prospective, and echocardiography-based study. Consecutive HFmrEF patients, defined as HF patients with a left ventricular ejection fraction (LVEF) between 40 and 49%, between January 2016 to December 2021 were included. Echocardiography was re-examined at 3-, 6-, and 12-month follow-up to assess the LVRR dynamically. Body mass index (BMI), fat mass, fat-free mass, percent body fat (PBF), CUN-BAE index, and lean mass index (LMI) were adopted as anthropometric parameters in our study to assess body composition. The primary outcome was LVRR, defined as: (1) a reduction higher than 10% in LV end-diastolic diameter index (LVEDDI), or a LVEDDI < 33 mm/m2, (2) an absolute increase of LVEF higher than 10 points compared with baseline echocardiogram, or a follow-up LVEF ≥50%. The secondary outcome was a composite of re-hospitalization for HF or cardiovascular death. RESULTS: A total of 240 HFmrEF patients were enrolled in our formal analysis. After 1-year follow-up based on echocardiography, 113 (47.1%) patients developed LVRR. Patients with LVRR had higher fat mass (21.7 kg vs. 19.3 kg, P = 0.034) and PBF (28.7% vs. 26.6%, P = 0.047) compared with those without. The negative correlation between anthropometric parameters and baseline LVEDDI was significant (all P < 0.05). HFmrEF patients with higher BMI, fat mass, PBF, CUN-BAE index, and LMI had more pronounced and persistent increase of LVEF and decline in LV mass index (LVMI). Univariable Cox regression analysis revealed that higher BMI (HR 1.042, 95% CI 1.002-1.083, P = 0.037) and fat mass (HR 1.019, 95% CI 1.002-1.036, P = 0.026) were each significantly associated with higher cumulative incidence of LVRR for HFmrEF patients, while this relationship vanished in the adjusted model. Mediation analysis indicated that the association between BMI and fat mass with LVRR was fully mediated by baseline LV dilation. Furthermore, higher fat mass (aHR 0.957, 95% CI 0.917-0.999, P = 0.049) and PBF (aHR 0.963, 95% CI 0.924-0.976, P = 0.043) was independently associated with lower risk of adverse clinical events. CONCLUSIONS: Body composition played an important role in the LVRR and clinical outcomes for HFmrEF. For HFmrEF patients, BMI and fat mass was positively associated with the cumulative incidence of LVRR, while higher fat mass and PBF predicted lower risk of adverse clinical events but not LMI.

The association between triglyceride glucose index and gout: a cross-sectional analysis based on NHANES 2007-2018.

BACKGROUND: The triglyceride glucose (TyG) index, defined as Ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2], provides insights into overall metabolic status. However, the association between the TyG index and gout has not been investigated. Therefore, this study explored the correlation between the TyG index and gout. METHODS: Using data from the National Health and Nutrition Examination Survey, which was conducted from 2007 to 2018, this study investigated the relationship between the TyG index and gout. Demographic data and potential risk factors were analyzed and compared using t tests for continuous data and chi-square tests for categorical data. Logistic regression and subgroup analysis were performed to examine the association between the TyG index and gout. RESULTS: A total of 14,924 participants were enrolled, among whom 726 (4.86%) were diagnosed with gout. Without controlling for any covariates, a significant positive correlation was observed between an elevated TyG index and increased risk of gout, with an odds ratio (OR) of 2.07 and a 95% confidence interval (CI) ranging from 1.76 to 2.43. After full adjustment, this association remained statistically significant, with an adjusted OR of 1.43 and a 95% CI from 1.14 to 1.80. Subgroup analyses revealed significant interactions, particularly for females (OR = 2.55; 95% CI: 2.00-3.26), individuals with no military service history (OR = 2.15; 95% CI: 1.66-2.43), and those without diabetes (OR = 2.00; 95% CI: 1.64-2.43). CONCLUSION: A positive correlation was observed between the TyG index and gout. Consequently, further large-scale prospective studies are warranted for a comprehensive analysis of the role of the TyG index in gout.

Seasonal hydrological dynamics affected the diversity and assembly process of the antibiotic resistome in a canal network.

The significant threat of antibiotic resistance genes (ARGs) to aquatic environments health has been widely acknowledged. To date, several studies have focused on the distribution and diversity of ARGs in a single river while their profiles in complex river networks are largely known. Here, the spatiotemporal dynamics of ARG profiles in a canal network were examined using high-throughput quantitative PCR, and the underlying assembly processes and its main environmental influencing factors were elucidated using multiple statistical analyses. The results demonstrated significant seasonal dynamics with greater richness and relative abundance of ARGs observed during the dry season compared to the wet season. ARG profiles exhibited a pronounced distance-decay pattern in the dry season, whereas no such pattern was evident in the wet season. Null model analysis indicated that deterministic processes, in contrast to stochastic processes, had a significant impact on shaping the ARG profiles. Furthermore, it was found that Firmicutes and pH emerged as the foremost factors influencing these profiles. This study enhanced our comprehension of the variations in ARG profiles within canal networks, which may contribute to the design of efficient management approaches aimed at restraining the propagation of ARGs.

Magnesium malate-modified calcium phosphate bone cement promotes the repair of vertebral bone defects in minipigs via regulating CGRP.

Active artificial bone substitutes are crucial in bone repair and reconstruction. Calcium phosphate bone cement (CPC) is known for its biocompatibility, degradability, and ability to fill various shaped bone defects. However, its low osteoinductive capacity limits bone regeneration applications. Effectively integrating osteoinductive magnesium ions with CPC remains a challenge. Herein, we developed magnesium malate-modified CPC (MCPC). Incorporating 5% magnesium malate significantly enhances the compressive strength of CPC to (6.18 ± 0.49) MPa, reduces setting time and improves disintegration resistance. In vitro, MCPC steadily releases magnesium ions, promoting the proliferation of MC3T3-E1 cells without causing significant apoptosis, proving its biocompatibility. Molecularly, magnesium malate prompts macrophages to release prostaglandin E2 (PGE2) and synergistically stimulates dorsal root ganglion (DRG) neurons to synthesize and release calcitonin gene-related peptide (CGRP). The CGRP released by DRG neurons enhances the expression of the key osteogenic transcription factor Runt-related transcription factor-2 (RUNX2) in MC3T3-E1 cells, promoting osteogenesis. In vivo experiments using minipig vertebral bone defect model showed MCPC significantly increases the bone volume fraction, bone density, new bone formation, and proportion of mature bone in the defect area compared to CPC. Additionally, MCPC group exhibited significantly higher levels of osteogenesis and angiogenesis markers compared to CPC group, with no inflammation or necrosis observed in the hearts, livers, or kidneys, indicating its good biocompatibility. In conclusion, MCPC participates in the repair of bone defects in the complex post-fracture microenvironment through interactions among macrophages, DRG neurons, and osteoblasts. This demonstrates its significant potential for clinical application in bone defect repair.

TRIM13 Reduces Damage to Alveolar Epithelial Cells in COPD by Inhibiting Endoplasmic Reticulum Stress-Induced ER-Phagy.

PURPOSE: Tripartite motif-containing protein 13 (TRIM13) directly or indirectly participates in autophagy and apoptosis. However, it remains unclear whether TRIM13 participates in chronic obstructive pulmonary disease (COPD) progression. This study aimed to reveal the molecular mechanisms through which TRIM13 regulates alveolar epithelial cell injury in COPD to provide new molecular targets for COPD treatment. METHODS: The TRIM13 expression levels were determined in clinical COPD patients and a rat emphysema model. A cigarette smoke-induced model of endoplasmic reticulum stress (ERS) and endoplasmic reticulum autophagy (ER-phagy) was developed using A549 cells, and the effects of TRIM13 gene overexpression/knockdown on ERS, ER-phagy, and cell apoptosis were assessed in these cells. RESULTS: TRIM13 expression was significantly decreased in the lung tissues of COPD patients and rats with emphysema. Moreover, the apoptosis level was significantly increased in the lung tissues of rats with emphysema. TRIM13 gene overexpression reduced the expression levels of ERS-related molecules (GRP78, GRP94, XBP-1, and eIF2a) in the COPD model; it also lowered the ER-phagy level, as evidenced by decreased number of autolysosomes observed by transmission electron microscopy, improved endoplasmic reticulum structure, reduced LC3-II/LC3-I and Beclin1 expression levels, and increased expression level of the autophagy inhibitory molecule Bcl-2. TRIM13 gene knockdown, however, led to opposite results. CONCLUSION: TRIM13 expression attenuated alveolar epithelial cell injury in COPD by inhibiting ERS-induced ER-phagy.

Targeting programmed cell death in inflammatory bowel disease through natural products: New insights from molecular mechanisms to targeted therapies.

Inflammatory bowel disease (IBD) is an autoimmune disorder primarily characterized by intestinal inflammation and recurrent ulceration, leading to a compromised intestinal barrier and inflammatory infiltration. This disorder's pathogenesis is mainly attributed to extensive damage or death of intestinal epithelial cells, along with abnormal activation or impaired death regulation of immune cells and the release of various inflammatory factors, which contribute to the inflammatory environment in the intestines. Thus, maintaining intestinal homeostasis hinges on balancing the survival and functionality of various cell types. Programmed cell death (PCD) pathways, including apoptosis, pyroptosis, autophagy, ferroptosis, necroptosis, and neutrophil extracellular traps, are integral in the pathogenesis of IBD by mediating the death of intestinal epithelial and immune cells. Natural products derived from plants, fruits, and vegetables have shown potential in regulating PCD, offering preventive and therapeutic avenues for IBD. This article reviews the role of natural products in IBD treatment by focusing on targeting PCD pathways, opening new avenues for clinical IBD management.

Research on Oracle Technology Based on Multi-Threshold Aggregate Signature Algorithm and Enhanced Trustworthy Oracle Reputation Mechanism.

In the realm of IoT sensor data security, particularly in areas like agricultural product traceability, the challenges of ensuring product origin and quality are paramount. This research presents a novel blockchain oracle solution integrating an enhanced MTAS signature algorithm derived from the Schnorr signature algorithm. The key improvement lies in the automatic adaptation of flexible threshold values based on the current scenario, catering to diverse security and efficiency requirements. Utilizing the continuously increasing block height of the blockchain as a pivotal blinding parameter, our approach strengthens signature verifiability and security. By combining the block height with signature parameters, we devise a distinctive signing scheme reliant on a globally immutable timestamp. Additionally, this study introduces a reliable oracle reputation mechanism for monitoring and assessing oracle node performance, maintaining both local and global reputations. This mechanism leverages smart contracts to evaluate each oracle's historical service, penalizing or removing nodes engaged in inappropriate behaviors. Experimental results highlight the innovative contributions of our approach to enhancing on-chain efficiency and fortifying security during the on-chain process, offering promising advancements for secure and efficient IoT sensor data transmission.

Improved Small Object Detection Algorithm CRL-YOLOv5.

Detecting small objects in images poses significant challenges due to their limited pixel representation and the difficulty in extracting sufficient features, often leading to missed or false detections. To address these challenges and enhance detection accuracy, this paper presents an improved small object detection algorithm, CRL-YOLOv5. The proposed approach integrates the Convolutional Block Attention Module (CBAM) attention mechanism into the C3 module of the backbone network, which enhances the localization accuracy of small objects. Additionally, the Receptive Field Block (RFB) module is introduced to expand the model's receptive field, thereby fully leveraging contextual information. Furthermore, the network architecture is restructured to include an additional detection layer specifically for small objects, allowing for deeper feature extraction from shallow layers. When tested on the VisDrone2019 small object dataset, CRL-YOLOv5 achieved an mAP50 of 39.2%, representing a 5.4% improvement over the original YOLOv5, effectively boosting the detection precision for small objects in images.

Functional Characterization of the Gibberellin (GA) Receptor ScGID1 in Sugarcane.

Sugarcane smut caused by Sporisorium scitamineum represents the most destructive disease in the sugarcane industry, causing host hormone disruption and producing a black whip-like sorus in the apex of the stalk. In this study, the gibberellin metabolic pathway was found to respond to S. scitamineum infection, and the contents of bioactive gibberellins were significantly reduced in the leaves of diseased plants. The gibberellin receptor gene ScGID1 was identified and significantly downregulated. ScGID1 localized in both the nucleus and cytoplasm and had the highest expression level in the leaves. Eight proteins that interact with ScGID1 were screened out using a yeast two-hybrid assay. Novel DELLA proteins named ScGAI1a and ScGA20ox2, key enzymes in GA biosynthesis, were both found to interact with ScGID1 in a gibberellin-independent manner. Transcription factor trapping with a yeast one-hybrid system identified 50 proteins that interacted with the promoter of ScGID1, among which ScS1FA and ScPLATZ inhibited ScGID1 transcription, while ScGDSL promoted transcription. Overexpression of ScGID1 in transgenic Nicotiana benthamiana plants could increase plant height and promote flowering. These results not only contribute to improving our understanding of the metabolic regulatory network of sugarcane gibberellin but also expand our knowledge of the interaction between sugarcane and pathogens.

Investigation on YSZ- and SiO2-Doped Mn-Fe Oxide Granules Based on Drop Technique for Thermochemical Energy Storage.

The Mn-Fe oxide material possesses the advantages of abundant availability, low cost, and non-toxicity as an energy storage material, particularly addressing the limitation of sluggish reoxidation kinetics observed in pure manganese oxide. However, scaling up the thermal energy storage (TCES) system poses challenges to the stability of the reactivities and mechanical strength of materials over long-term cycles, necessitating their resolution. In this study, Mn-Fe granules were fabricated with a diameter of approximately 2 mm using the feasible and scalable drop technique, and the effects of Y2O3-stabilized ZrO2 (YSZ) and SiO2 doping, at various doping ratios ranging from 1-20 wt%, were investigated on both the anti-sintering behavior and mechanical strength. In a thermal gravimetric analyzer, the redox reaction tests showed that both the dopants led to an enhancement in the reoxidation rates when the doping ratios were in an appropriate range, while they also brought about a decrease in the reduction rate and energy storage density. In a packed-bed reactor, the results of five consecutive redox tests showed a similar pattern to that in a thermal gravimetric analyzer. Additionally, the doping led to the stable reduction/oxidation reaction rates during the cyclic tests. In the subsequent 120 cyclic tests, the Si-doped granules exhibited volume expansion with a decreased crushing strength, whereas the YSZ-doped granules experienced drastic shrinkage with an increase in the crushing strength. The 1 wt% Si and 2 wt% Si presented the best synthetic performance, which resulted from the milder sintering effects during the long-term cyclic tests.

Effects of Trimethylamine N-Oxide in Improving Exercise Performance in Mice: A 1H-NMR-Based Metabolomic Analysis Approach.

To improve exercise performance, the supplement of nutrients has become a common practice before prolonged exercise. Trimethylamine N-oxide (TMAO) has been shown to ameliorate oxidative stress damage, which may be beneficial in improving exercise capacity. Here, we assessed the effects of TMAO on mice with exhaustive swimming, analyzed the metabolic changes, and identified significantly altered metabolic pathways of skeletal muscle using a nuclear magnetic resonance-based (NMR-based) metabolomics approach to uncover the effects of TMAO improving exercise performance of mice. We found that TMAO pre-administration markedly prolonged the exhaustive time in mice. Further investigation showed that TMAO pre-administration increased levels of 3-hydroxybutyrate, isocitrate, anserine, TMA, taurine, glycine, and glutathione and disturbed the three metabolic pathways related to oxidative stress and protein synthesis in skeletal muscle. Our results provide a metabolic mechanistic understanding of the effects of TMAO supplements on the exercise performance of skeletal muscle in mice. This work may be beneficial in exploring the potential of TMAO to be applied in nutritional supplementation to improve exercise performance. This work will lay a scientific foundation and be beneficial to exploring the potential of TMAO to apply in nutritional supplementation.