Resistance exercise preconditioning prevents disuse muscle atrophy by inhibiting apoptosis and protein degradation via SESN2 in C57BL/6J mice.

AIM: To compare the effects of different exercise preconditioning in the context of skeletal muscle atrophy and to investigate the potential involvement of Sestrin2 (SESN2), a stress-inducible protein that can be regulated by exercise, in exercise preconditioning on preventing disuse muscle atrophy. METHODS: Eight-week-old male C57BL/6J mice were randomly assigned to sedentary groups (SD), aerobic exercise groups (AE), resistance exercise groups (RE), and combined exercise groups (CE) with or without 7 days of immobilization. The duration of the exercise intervention was 10 weeks. The effects of different exercise preconditioning to prevent muscle atrophy were analyzed by evaluating skeletal muscle function and mass. Additionally, to investigate the potential underlying mechanism of exercise-induced protection of skeletal muscle, wild-type and SESN2--/-- mice were randomly divided into sedentary group and resistance exercise preconditioning group. C2C12 cells were treated with SESN2 adenoviruses and MK2206 (an AKT inhibitor) for 48 h to elucidate the underlined mechanism. RESULTS: RE was more effective in preserving skeletal muscle function, muscle mass and maintaining skeletal muscle protein homeostasis than AE and CE under immobilized condition. Importantly, exercise performance, muscle mass to body weight ratio, and the cross-sectional area of muscle fibers were significantly lower in SESN2-/- mice than wild-type mice after resistance exercise preconditioning. Mechanistically, the absence of SESN2 led to activation of the ubiquitin-proteasome system and induction of apoptosis. In vitro experiments showed that MK2206 treatment mitigated the regulatory effects of overexpression-SESN2 on protein hydrolysis and apoptosis. CONCLUSION: RE was more effective than AE or CE in preventing disuse muscle atrophy. SESN2 mediated the protective effects of resistance exercise preconditioning on skeletal muscle atrophy.

Speckle noise suppression method in a holographic display based on pixel processing.

In this paper, we propose a method to suppress the speckle noise in a holographic display based on pixel processing. Through the separation of object pixels in space, the recorded object is divided into multiple object point groups. The complex amplitude of the light field for each object point group is recorded as a sub-computer-generated hologram (sub-CGH). The phase of each pixel on a sub-CGH is optimized to generate the final sub-CGH. Therefore, the pixels of the recorded object and sub-CGH are processed. In the reconstruction process, the final sub-CGHs are loaded on the spatial light modulator sequentially. The speckle noise of the reconstructed image is suppressed by reducing the algorithm error and the overlapping area of adjacent image points. The experimental results prove the feasibility of the proposed method.

Development of an Evaluation System for the Prophylactic Use of Antimicrobial Drugs in the Perioperative Period of Class I Surgical Incisions in Neurosurgery.

BACKGROUND: This study aimed to establish a precise preoperative high-risk factor scoring system and algorithm for antibiotic prophylaxis decision-making, provide guidance for the judicious use of AMP, refine interventions, and ensure the appropriate application of AMP for class I incisions in neurosurgery. METHODS: According to PRISMA guidelines, literature searches, study selection, methodology development, and quality appraisal were performed. The quality of evidence across the study population was assessed using the Newcastle-Ottawa Scale. A two-round Delphi expert consultation method involved 15 experts from leading tertiary hospitals in China. Establishing an algorithm of SOPs for perioperative antimicrobial prophylaxis in Class I neurosurgical incisions. RESULTS: Thirteen studies, encompassing 11,936 patients undergoing clean neurosurgical procedures, were included. 791 patients experienced SSI, resulting in an average incidence of 6.62%. Identified risk factors significantly associated with an increased incidence of postoperative SSI (P < 0.05) included emergency surgery, preoperative hospitalization ≥7 days, intraoperative blood loss ≥300 mL, operation time ≥4 hours, diabetes mellitus, cerebrospinal fluid leakage, and repeat surgery. Sensitivity analysis demonstrated robust results for emergency surgery, intraoperative blood loss ≥300 mL, operation time ≥4 hours, cerebrospinal fluid leakage, and repeat surgery. Established a risk assessment system for Class I neurosurgical incisions by the Delphi method. Additionally, we have formulated an algorithm of SOPs for perioperative antimicrobial prophylaxis in Class I neurosurgical incisions. CONCLUSIONS: The established index for AMP utilization and SOPs in the preoperative period of class I neurosurgical incisions proves valuable, contributing to improved patient outcomes in neurosurgical procedures.

A conserved protein inhibitor brings under check the activity of RNase E in cyanobacteria.

The bacterial ribonuclease RNase E plays a key role in RNA metabolism. Yet, with a large substrate spectrum and poor substrate specificity, its activity must be well controlled under different conditions. Only a few regulators of RNase E are known, limiting our understanding on posttranscriptional regulatory mechanisms in bacteria. Here we show that, RebA, a protein universally present in cyanobacteria, interacts with RNase E in the cyanobacterium Anabaena PCC 7120. Distinct from those known regulators of RNase E, RebA interacts with the catalytic region of RNase E, and suppresses the cleavage activities of RNase E for all tested substrates. Consistent with the inhibitory function of RebA on RNase E, depletion of RNase E and overproduction of RebA caused formation of elongated cells, whereas the absence of RebA and overproduction of RNase E resulted in a shorter-cell phenotype. We further showed that the morphological changes caused by altered levels of RNase E or RebA are dependent on their physical interaction. The action of RebA represents a new mechanism, potentially conserved in cyanobacteria, for RNase E regulation. Our findings provide insights into the regulation and the function of RNase E, and demonstrate the importance of balanced RNA metabolism in bacteria.

SPA, a Stigma-style-transmitting tract Physical microenvironment Assay for investigating mechano-signaling in pollen tubes.

Accurate sensing and responding to physical microenvironment are crucial for cell function and survival, but the underlying molecular mechanisms remain elusive. Pollen tube (PT) provides a perfect single-cell model for studying mechanobiology since it's naturally subjected to complex mechanical instructions from the pistil during invasive growth. Recent reports have revealed discrepant PT behaviors between in vivo and flat, two-dimensional in vitro cultures. Here, we established the Stigma-style-transmitting tract (TT) Physical microenvironment Assay (SPA) to recapitulate pressure changes in the pistil. This biomimetic assay has enabled us to swiftly identify highly redundant genes, GEF8/9/11/12/13, as new regulators for maintaining PTs integrity during style-to-TT emergence. In contrast to normal growth on solid medium, SPA successfully phenocopied gef8/9/11/12/13 PT in vivo growth-arrest deficiency. Our results suggest the existence of distinct signaling pathways regulating in vivo and in vitro PT integrity maintenance, underscoring the necessity of faithfully mimicking the physical microenvironment for studying plant cell biology.

Conjugation Length-Dependent Raman Scattering Intensity of Conjugated Polymers.

Polydiacetylenes, as a class of conjugated polymers with alternating conjugated C═C and C≡C bonds, have emerged as a promising probe material for biomedical Raman imaging, given their ultrastrong Raman scattering intensity. However, the relationship between the structure, especially the molecular length of polydiacetylenes, and their Raman scattering intensity remains unclear. In this work, a series of water-soluble polydiacetylenes, namely poly(deca-4,6-diynedioic acid) (PDDA) with different molecular weights (MWs), is prepared through controlled polymerization and degradation. The ultraviolet-visible (UV-vis) absorption spectroscopic and Raman spectroscopic studies on these polymers reveal that the Raman scattering intensity of PDDA increases nonlinearly with the MW. The MW-Raman scattering intensity relationship in the polymerization process is completely different from that in the degradation process. In contrast, the Raman scattering intensity increases more linearly with the maximal absorbance of the polymer, and the relationship between the Raman scattering intensity and the maximal absorbance of PDDA in the polymerization process is consistent with that in the degradation process. The Raman scattering intensity of PDDA hence exhibits a better dependence on the effective conjugation length of the polymer, which should guide the future design of conjugated polymers for Raman imaging applications.

Resistance exercise alleviates dexamethasone-induced muscle atrophy via Sestrin2/MSTN pathway in C57BL/6J mice.

AIM: It has long been recognized that resistance exercise can substantially increase skeletal muscle mass and strength, but whether it can protect against glucocorticoid-induced muscle atrophy and its potential mechanism is yet to be determined. This study aimed to investigate the protective effects of resistance exercise in dexamethasone-induced muscle atrophy and elucidate the possible function of exercise-induced protein Sestrin2 in this process. METHODS: Eight-week-old male C57BL/6J mice carried out the incremental mouse ladder exercise for 11 weeks. Two weeks before the end of the intervention, mice were daily intraperitoneally injected with dexamethasone. Body composition, muscle mass, and exercise performance were examined to evaluate muscle atrophy. In vitro, C2C12 cells were used for RT-qPCR, Western Blot, and immunofluorescence experiments to elucidate the potential mechanism. RESULTS: Our results showed that long-term resistance exercise is an effective intervention for dexamethasone-induced muscle atrophy. We also found that Sestrin2 plays a vital role in dexamethasone-induced muscle atrophy. In both animal (P = .0006) and cell models (P = .0266), dexamethasone intervention significantly reduced the protein expression of Sestrin2, which was increased (P = .0112) by resistance exercise. Inversely, overexpression of Sestrin2 improved (P < .0001) dexamethasone-induced myotube cell atrophy by reducing the activation of the ubiquitin-proteasome pathway via inhibiting Forkhead box O3 (FoxO3a) and myostatin (MSTN)/small mother against decapentaplegic (Smad) signaling pathways. CONCLUSION: Taken together, our results indicated that Sestrin2 may serve as an effective molecule that mimics the protective effect of resistance exercise on dexamethasone-induced muscle atrophy.

Exercise ameliorates chronic inflammatory response induced by high-fat diet via Sestrin2 in an Nrf2-dependent manner.

Chronic inflammation is a major contributor to the development of metabolic disorders and is commonly seen in studies of diet-induced obesity in humans and rodents. Exercise has been shown to have anti-inflammatory properties, though the exact mechanisms are still not fully understood. Sestrins and Nrf2 are of interest to researchers as they are known to protect against inflammation and oxidative stress. In this study, we aim to explore the interconnection between Sestrin2 (SESN2) and Nrf2 and their roles in exercise benefits on chronic inflammation. Our data showed that SESN2 knockout aggravated the abnormalities of body weight, fat mass, and serum lipid that were induced by a high-fat diet (HFD), and a concomitant increase of TNF-α, IL-1ß and IL-6 in both serum and skeletal muscle. Notably, exercise was found to reverse these changes, and SESN2 was found to be necessary for exercise to reduce the inflammatory response in skeletal muscles, though not in serum. Immunoprecipitation and bioinformatics prediction experiments further revealed that SESN2 directly binds to Nrf2, indicating a protein-protein interaction between the two. Furthermore, our data demonstrated that SESN2 protein is necessary for exercise-induced effects on Nrf2 pathway in HFD-fed mice, and Nrf2 protein is necessary to enable SESN2 to reduce the inflammation caused by palmitic acid (PA)+ oleic acid (OA) treatment in vitro. Our findings indicate that exercise mitigates chronic inflammation induced by HFD through SESN2 in an Nrf2-dependent manner. Our study reveals a novel molecular mechanism whereby the SESN2/Nrf2 pathway mediates the positive impact of exercise on chronic inflammation.

Engine remaining useful life prediction model based on R-Vine copula with multi-sensor data.

Aeroengine is a highly complex and precise mechanical system. As the heart of an aircraft, it has a crucial impact on the overall life of the aircraft. Engine degradation process is caused by multiple factors, so multi-sensor signals are used for condition monitoring and prognostics of engine performance degradation. Compared with the single sensor signal, the multi-sensor signals can more comprehensively contain the degradation information of the engine and achieve higher prediction accuracy of the remaining useful life (RUL). Therefore, a new method for predicting the RUL of an engine based on R-Vine Copula under multi-sensor data is proposed. Firstly, aiming at the phenomenon that the engine performance parameters change over time, and the performance degradation presents nonlinear characteristics, the nonlinear Wiener process is used to model the degradation process of a single degradation signal. Secondly, the model parameters are estimated in the offline stage to integrate the historical data to obtain the offline parameters of the model. In the online stage, when the real-time data is obtained, the Bayesian method is used to update the model parameters. Then, the R-Vine Copula is used to model the correlation between multi-sensor degradation signals to realize online prediction of the remaining useful life of the engine. Finally, the C-MAPSS dataset is selected to verify the effectiveness of the proposed method. The experimental results show that the proposed method can effectively improve prediction accuracy.

Globular adiponectin ameliorates insulin resistance in skeletal muscle by enhancing the LKB1-mediated AMPK activation via SESN2.

Adiponectin has been demonstrated to be a mediator of insulin sensitivity; however, the underlined mechanisms remain unclear. SESN2 is a stress-inducible protein that phosphorylates AMPK in different tissues. In this study, we aimed to validate the amelioration of insulin resistance by globular adiponectin (gAd) and to reveal the role of SESN2 in the improvement of glucose metabolism by gAd. We used a high-fat diet-induced wild-type and SESN2-/- C57BL/6J insulin resistance mice model to study the effects of six-week aerobic exercise or gAd administration on insulin resistance. In vitro study, C2C12 myotubes were used to determine the potential mechanism by overexpressing or inhibiting SESN2. Similar to exercise, six-week gAd administration decreased fasting glucose, triglyceride and insulin levels, reduced lipid deposition in skeletal muscle and reversed whole-body insulin resistance in mice fed on a high-fat diet. Moreover, gAd enhanced skeletal muscle glucose uptake by activating insulin signaling. However, these effects were diminished in SESN2-/- mice. We found that gAd administration increased the expression of SESN2 and Liver kinase B1 (LKB1) and increased AMPK-T172 phosphorylation in skeletal muscle of wild-type mice, while in SESN2-/- mice, LKB1 expression was also increased but the pAMPK-T172 was unchanged. At the cellular level, gAd increased cellular SESN2 and pAMPK-T172 expression. Immunoprecipitation experiment suggested that SESN2 promoted the formation of complexes of AMPK and LKB1 and hence phosphorylated AMPK. In conclusion, our results revealed that SESN2 played a critical role in gAd-induced AMPK phosphorylation, activation of insulin signaling and skeletal muscle insulin sensitization in mice with insulin resistance.

Multivalent Nanobody Conjugate with Rigid, Reactive Oxygen Species Scavenging Scaffold for Multi-Target Therapy of Alzheimer's Disease.

Efficient therapeutic strategies that concurrently target both Aß aggregation and oxidative stress in the Alzheimer's disease (AD) microenvironment emerge as a cutting-edge tool to combat the intricate pathogenesis of AD. Here, a multivalent nanobody conjugate with rigid, reactive oxygen species (ROS) scavenging scaffold is developed to achieve simultaneous Aß amyloidogenesis mitigation, ROS elimination, and Aß plaque clearance. Grafting Aß segment (33-GLMVGGVVIA-42) into the third complementary-determining region of a parent nanobody generates an engineered nanobody NB that can recognize Aß and inhibit its aggregation through homotypic interactions. NB is further genetically modified with a fragment of human interleukin-1ß (163-VQGEESNDK-171), so that the obtained fusion nanobody NBIL can also facilitate the Aß clearance by microglia. Linking NBIL covalently onto a rigid, ROS scavenging scaffold poly(deca-4,6-diynedioic acid) (PDDA) creates the multivalent nanobody conjugate PNBIL, which not only boosts the binding affinity between NBIL and Aß aggregates for nearly 100 times but also possesses a long-term capability of oxidative stress alleviation, inflammation reduction, and neuron protection. PNBIL has significantly attenuated symptoms on two AD mouse models through amyloidogenesis inhibition and AD microenvironment modulation, validating that the multivalent nanobody conjugate design based on combinatory nanobody and molecular engineering is a promising approach of multi-target therapeutic strategies.

Aerobic exercise ameliorates insulin resistance in C57BL/6 J mice via activating Sestrin3.

Skeletal muscle insulin resistance (IR) is closely linked to hyperglycemia and metabolic disorders. Regular exercise enhances insulin sensitivity in skeletal muscle, but its underlying mechanisms remain unknown. Sestrin3 (SESN3) is a stress-inducible protein that protects against obesity-induced hepatic steatosis and insulin resistance. Regular exercise training is known to increase SESN3 expression in skeletal muscle. The purpose of this study was to explore whether SESN3 mediates the metabolic effects of exercise in the mouse model of high-fat diet (HFD)-induced IR. SESN3-/- mice exhibited severer body weight gain, ectopic lipid accumulation, and dysregulation of glucose metabolism after long-term HFD feeding compared with the wild-type (WT) mice. Moreover, we found that SESN3 deficiency weakened the effects of exercise on reducing serum insulin levels and improving glucose tolerance in mice. Exercise training increased pAKT-S473 and GLUT4 expression, accompanied by enhanced pmTOR-S2481 (an indicator of mTORC2 activity) in WT quadriceps that were less pronounced in SESN3-/- mice. SESN3 overexpression in C2C12 myotubes further confirmed that SESN3 played an important role in skeletal muscle glucose metabolism. SESN3 overexpression increased the binding of Rictor to mTOR and pmTOR-S2481 in C2C12 myotubes. Moreover, SESN3 overexpression resulted in an elevation of glucose uptake and a concomitant increase of pAKT-S473 in C2C12 myotubes, whereas these effects were diminished by downregulation of mTORC2 activity. Taken together, SESN3 is a crucial protein in amplifying the beneficial effects of exercise on insulin sensitivity in skeletal muscle and systemic glucose levels. SESN3/mTORC2/AKT pathway mediated the effects of exercise on skeletal muscle insulin sensitivity.

Two similar carbon monoxide poisoning cases with different outcomes: evidence from longitudinal fMRI.

Prognosis after carbon monoxide (CO) poisoning is difficult to assess using structural images. Functional connectivity provided by functional magnetic resonance imaging (fMRI) may explain the mechanism of differential prognosis. We report here two cases of carbon monoxide poisoning with simultaneous coma. They were nearly normal on days 7-8, but diagnosed with delayed neurological sequelae (DNS) with cognitive and motor impairments on days 22-29. Similar Methylprednisolone pulse therapy and hyperbaric oxygen therapy were given to them. The movement disorder of case 1 improved slightly during the recovery stage, while the movement disorder of case 2 worsened significantly. In case 1, the function of supplementary motor area decreased first and then increased, and the function of pallidum increased first and then decreased. Case 2 showed a reduction in the supplementary motor area and small changes in the pallidum after DNS, but both were reduced during recovery stage. The cognitive ability of case 1 remained poor, while that of case 2 improved during the recovery stage. FMRI showed damage to the right and bilateral hippocampus in case 1 and partial damage to the left hippocampus in case 2. Taken together, fMRI can be a useful method to study functional connectivity abnormalities corresponding to different prognoses.

Combined cell grafting and VPA administration facilitates neural repair through axonal regeneration and synaptogenesis in traumatic brain injury.

Neuronal regeneration and functional recovery are severely compromised following traumatic brain injury (TBI). Treatment options, including cell transplantation and drug therapy, have been shown to benefit TBI, although the underlying mechanisms remain elusive. In this study, neural stem cells (NSCs) are transplanted into TBI-challenged mice, together with olfactory ensheathing cells (OECs) or followed by valproic acid (VPA) treatment. Both OEC grafting and VPA treatment facilitate the differentiation of NSCs into neurons (including endogenous and exogenous neurons) and significantly attenuate neurological functional defects in TBI mice. Combination of NSCs with OECs or VPA administration leads to overt improvement in axonal regeneration, synaptogenesis, and synaptic plasticity in the cerebral cortex in TBI-challenged mice, as shown by retrograde corticospinal tract tracing, electron microscopy, growth-associated protein 43 (GAP43), and synaptophysin (SYN) analyses. However, these beneficial effects of VPA are reversed by local delivery of N-methyl-D-aspartate (NMDA) into tissues surrounding the injury epicenter in the cerebral cortex, accompanied by a pronounced drop in axons and synapses in the brain. Our findings reveal that increased axonal regeneration and synaptogenesis evoked by cell grafting and VPA fosters neural repair in a murine model of TBI. Moreover, VPA-induced neuroprotective roles are antagonized by exogenous NMDA administration and its concomitant decrease in the number of neurons of local brain, indicating that increased neurons induced by VPA treatment mediate axonal regeneration and synaptogenesis in mice after TBI operation. Collectively, this study provides new insights into NSC transplantation therapy for TBI.

Exercise improves high-fat diet-induced metabolic disorder by promoting HDAC5 degradation through the ubiquitin-proteasome system in skeletal muscle.

Histone deacetylase 4/5 (HDAC4/5) are essential for regulating metabolic gene expression; AMPKα2 regulates HDAC4/5 activity and the expression of MuRF1 during exercise. In this study, we used wild-type and AMPKα2-/- mice to explore the potential regulatory relationship between AMPKα2 and HDAC4/5 expression during exercise. Firstly, we fed C57BL/6J mice with high-fat diet for 8 weeks to assess the effects of high-fat diet on skeletal muscle metabolism and HDAC4/5 expression. We then performed a 6-week treadmill exercise on both wild-type and AMPKα2-/- mice. After exercise, the expressions of HDAC4/5 were examined in both gastrocnemius and soleus. The citrate synthase activity and proteins involved in skeletal muscle oxidative process were assessed. To determine the relationship of HDAC4/5 and skeletal muscle oxidative capacity, citrate synthase activity was assessed after silencing HDAC4/5. Moreover, HDAC5 ubiquitination and the association of MuRF1 to HDAC5 were also investigated. Our results showed that 6-week exercise increased the skeletal muscle oxidative capacity and decreased HDAC4/5 expression only in soleus. HDAC5 silencing increased C2C12 cell oxidative capacity. Proteasome inhibition by MG132 abolished exercise-induced HDAC5 degradation mediated by MuRF1-ubiquitin-proteasome system. However, the ubiquitin-proteasome system (UPS) did not dominantly account for exercise-induced HDAC4 degradation. Exercise upregulated MuRF1-HDAC5 association in wild-type mice but not in AMPKα2-/- mice. Our results revealed that 6-week exercise increased the skeletal muscle oxidative capacity and promoted HDAC5 degradation in soleus through the UPS, MuRF1-mediated HDAC5 ubiquitination. Although AMPKα2 played a partial role in regulating MuRF1 expression and HDAC5 ubiquitination, exercise-induced HDAC5 degradation did not fully depend on AMPKα2.

Genistein promotes M1 macrophage apoptosis and reduces inflammatory response by disrupting miR-21/TIPE2 pathway.

Cardiovascular diseases are a major cause of mortality, and vascular injury, a common pathological basis of cardiovascular disease, is deeply correlated with macrophage apoptosis and inflammatory response. Genistein, a type of phytoestrogen, exerts cardiovascular protective activities, but the underlying mechanism has not been fully elucidated. In this study, RAW264.7 cells were treated with genistein, lipopolysaccharide (LPS), nuclear factor-kappa B (NF-κB) inhibitor, and/or protein kinase B (AKT) agonist to determine the role of genistein in apoptosis and inflammation in LPS-stimulated cells. Simultaneously, high fat diet-fed C57BL/6 mice were administered genistein to evaluate the function of genistein on LPS-induced cardiovascular injury mouse model. Here, we demonstrated that LPS obviously increased apoptosis resistance and inflammatory response of macrophages by promoting miR-21 expression, and miR-21 downregulated tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) expression by targeting the coding region. Genistein reduced miR-21 expression by inhibiting NF-κB, then blocked toll-like receptor 4 (TLR4) pathway and AKT phosphorylation dependent on TIPE2, resulting in inhibition of LPS. Our research suggests that miR-21/TIPE2 pathway is involved in M1 macrophage apoptosis and inflammatory response, and genistein inhibits the progression of LPS-induced cardiovascular injury at the epigenetic level via regulating the promoter region of Vmp1 by NF-κB.

Exercise protects intestinal epithelial barrier from high fat diet- induced permeabilization through SESN2/AMPKα1/HIF-1α signaling.

Over-nutrition and a sedentary lifestyle are associated with increased intestinal permeability. This condition promotes obesity and associated metabolic disorders. Sestrin2 (SESN2) is a stress-inducible protein thought to promote the survival and recovery of epithelial cells and act as a positive regulator in exercise-induced improvements of glycolipid metabolism. Here we aimed to test the hypothesis that chronic exercise can protect intestinal barrier function against high-fat diet induced permeabilization through SESN2. WT and SESN2-/- mice were randomly assigned to five groups, fed with either normal chow or high fat diet (HFD), and provided with or without exercise training for 15-week. Metabolic parameters, fecal microbiota composition, and intestinal barrier integrity were assessed. The role of the gut microbiota was investigated by administering a mixture of broad-spectrum antibiotics (ABX). Fifteen-week HFD feeding induced dysmetabolism, dysbiosis and gut barrier dysfunctions in the WT mice. These effects were exaggerated in SESN2-/- mice. Chronic aerobic exercise significantly reversed HFD-induced pathologic changes, while SESN2 ablation weakened the protective effects of exercise. ABX did not abolish the differences in gut barrier function between WT and SESN2-/- mice. We speculated that SESN2 may protect intestinal integrity partly independent of gut microbiome. Combining ex vivo and in vivo approaches, we demonstrated that SESN2/pAMPK-Thr172/HIF-1α pathway may play an important role in exercise- improved intestinal permeability. Taken together, our study demonstrated that HFD and SESN2-KO have synergistic effects on intestinal homeostasis. SESN2 is crucial in exercise-improved intestinal permeability.

Alterations of Lysine Acetylation Profile in Murine Skeletal Muscles Upon Exercise.

Objective: Regular exercise is a powerful tool that enhances skeletal muscle mass and strength. Lysine acetylation is an important post-translational modification (PTM) involved in a broad array of cellular functions. Skeletal muscle protein contains a considerable number of lysine-acetylated (Kac) sites, so we aimed to investigate the effects of exercise-induced lysine acetylation on skeletal muscle proteins. Methods: We randomly divided 20 male C57BL/6 mice into exercise and control groups. After 6 weeks of treadmill exercise, a lysine acetylation proteomics analysis of the gastrocnemius muscles of mice was performed. Results: A total of 2,254 lysine acetylation sites in 693 protein groups were identified, among which 1,916 sites in 528 proteins were quantified. The enrichment analysis suggested that protein acetylation could influence both structural and functional muscle protein properties. Moreover, molecular docking revealed that mimicking protein deacetylation primarily influenced the interaction between substrates and enzymes. Conclusion: Exercise-induced lysine acetylation appears to be a crucial contributor to the alteration of skeletal muscle protein binding free energy, suggesting that its modulation is a potential approach for improving exercise performance.

Sestrin2 ablation attenuates the exercise-induced browning of white adipose tissue in C57BL/6J mice.

AIM: With exercise, white adipose tissues (WAT) are readily convertible to a "brown-like" state, altering from lipid-storing to energy-catabolizing function, which counteracts obesity and increases insulin sensitivity. Sestrin2 (SESN2) is a stress-inducible protein that can regulate the cold-induced increase of uncoupling protein 1 (UCP1), which is paramount for the thermogenic capacity of brown-like WAT. This study aimed to elucidate the necessity of SESN2 in mediating exercise-induced browning of WAT. METHODS: We used 8-week, male wild-type and SESN2 knockout C57BL/6J mice to explore the potential role of SESN2 in the exercise-induced WAT browning process. Over a 3-week intervention (sedentary versus treadmill exercise, normal chow versus 60% high-fat diet), we examined the exercise-induced alterations of the browning phenotype in different depots of white fat. In vitro, 3T3-L1 pre-adipocytes and primary adipocytes were used to determine the potential mechanism. RESULTS: Our data revealed that SESN2 was required for the exercise-induced subcutaneous WAT (scWAT) browning. This may be mediated by higher fibronectin type III domain containing 5 (FNDC5) contents in scWAT locally, rather than skeletal muscle FNDC5 expression and circulating serum irisin levels. SESN2 ablation significantly impaired the exercise-improved glucose metabolism, where browning of scWAT may serve as an essential pathway. Moreover, SESN2 ablation significantly attenuated the exercise-promoted respiratory exchange ratio and indexes of energy metabolism (oxygen uptake and energy expenditure). CONCLUSION: Taken together, our results provided evidence that SESN2 is a key integrating factor in driving the diverse metabolic benefits conferred by aerobic exercise.