A presumed missense variant in the U2AF2 gene causes exon skipping in neurodevelopmental diseases.

U2 small nuclear RNA auxiliary factor 2 (U2AF2) is an indispensable pre-mRNA splicing factor in the early process of splicing. Recently, U2AF2 was reported as a novel candidate gene associated with neurodevelopmental disorders. Herein, we report a patient with a novel presumed heterozygous missense variant in the U2AF2 gene (c.603G>T), who has a similar clinical phenotype as the patient reported before, including epilepsy, intellectual disability, language delay, microcephaly, and hypoplastic corpus callosum. We reviewed the phenotypic and genetic spectrum of patients with U2AF2-related neurological diseases, both newly diagnosed and previously reported. To investigate the possible pathogenesis, EBV-immortalized lymphoblastoid cells were derived from the peripheral blood obtained from the patient and control groups. Furthermore, according to the results of WB, RT-PCR, Q-PCR, and cDNA sequencing of RT-PCR products, the presumed missense variant c.603G>T caused exon 6 skipping in the U2AF2 mRNA transcript and led to a truncated protein (p.E163_E201del). Cell Counting Kit-8 (CCK-8) and cell cycle detection demonstrated that the variant c.603G>T inhibited the proliferation of patient lymphocyte cells compared with the control group. This study is aimed at expanding the phenotypic and genetic spectrum of U2AF2-related neurodevelopmental diseases and investigating the potential effects. This is the first report of the possible pathogenesis of a U2AF2 gene pathogenic variant in a patient with neurodevelopmental diseases and shows that a novel presumed missense variant in the U2AF2 gene causes exon skipping.

Exercise activates autophagy and regulates endoplasmic reticulum stress in muscle of high-fat diet mice to alleviate insulin resistance.

Exercise training has been demonstrated as an effective therapy for insulin resistance (IR) to relieve skeletal muscle metabolic disorders. Physiologic protective autophagy was found blocked by IR induced severe endoplasmic reticulum (ER) stress, which may lead to progression of IR. However, the mechanisms are not fully understood. Therefore, this study sought to investigate that how exercise training act on IR through an exploration into the mechanism of ER stress and high-fat diet (HFD)-blocked autophagy. A rodent model was adopted in mice via a HFD and an 8-week swim exercise training intervention. The mouse IR model was successfully established through HFD treatment: body mass, adipose weight, HOMA-IR index increased, as well as IRS1, inhibited in the muscle of HFD mice. Moreover, the AMPK/PGC1α pathway was depressed and IRE1, PERK, ATF6-related ER stress signaling was activated in the muscle of HFD mice. While autophagy factors, including BNIP3, LC3II/LC3I, and PINK1, decreased. However, additional 8-week exercise training during HFD was found to reverse all these changes and alleviate IR. Thus, exercise training could facilitate HFD-blocked protective autophagy via the activation of the AMPK/PGC1α pathway to relieve insulin resistance in mice. Our study provides experimental data for the prevention of T2DM and insulin resistance.

The role of losartan in preventing vascular remodeling in spontaneously hypertensive rats by inhibition of the H2O2/VPO1/HOCl/MMPs pathway.

Vascular peroxidase 1 (VPO1) has been proved to be associated with vascular endothelial cell apoptosis by producing reactive oxygen species. However, the contribution of VPO1 to the development of vascular remodeling (VR) remains to be fully characterized. We explored the role of VPO1 in VR in spontaneously hypertensive rats (SHRs) and the underlying mechanism of losartan in inhibiting VR. Compared to Wistar-Kyoto (WKY) rats, the SHR showed remodeling of their vascular walls. The level of VPO1 and the hydrogen peroxide (H2O2) concentration were increased in the SHRs. However, the SHRs pretreated with losartan showed significant inhibition of blood pressure and VR and decreased levels of VPO1 and H2O2 compared to the non-treated SHRs. Angiotensin II significantly increased the expressions of MMP-2, MMP-9 and the concentrations of H2O2 and hypochlorous acid (HOCl) in vascular smooth muscle cells (VSMCs). However, only the H2O2 level increased in VSMCs when transfected with VPO1 shRNA. These results support a critical but previously unrecognized role of VPO1 in VR and suggest that therapies to reduce VPO1 may be novel approaches for VR.

Preoperative exercise training decreases complications of minimally invasive lung cancer surgery: A randomized controlled trial.

OBJECTIVE: Limited evidence exists regarding the efficacy of preoperative exercise in reducing short-term complications after minimally invasive surgery in patients with non-small cell lung cancer. This study aims to investigate the impact of preoperative exercise on short-term complications after minimally invasive lung resection. METHODS: In this prospective, open-label, randomized (1:1) controlled trial at Xiangya Hospital, China (September 2020 to February 2022), patients were randomly assigned to a preoperative exercise group with 16-day alternate supervised exercise or a control group. The primary outcome assessed was short-term postoperative complications, with a follow-up period of 30 days postsurgery. RESULTS: A total of 124 patients were recruited (preoperative exercise group n = 62; control n = 62). Finally, 101 patients (preoperative exercise group; n = 51 and control; n = 50) with a median age of 56 years (interquartile range, 50-62 years) completed the study. Compared with the control group, the preoperative exercise group showed fewer postoperative complications (preoperative exercise 3/51 vs control 10/50; odds ratio, 0.17; 95% CI, 0.04-0.86; P = .03) and shorter hospital stays (mean difference, -2; 95% CI, -3 to -1; P = .01). Preoperative exercise significantly improved depression, stress, functional capacity, and quality of life (all P < .05) before surgery. Furthermore, preoperative exercise demonstrated a significantly lower minimum blood pressure during surgery and lower increases in body temperature on day 2 after surgery, neutrophil-to-lymphocyte ratio, and neutrophil count after surgery (all P < .05). Exploratory research on lung tissue RNA sequencing (5 in each group) showed downregulation of the tumor necrosis factor signaling pathway in the preoperative exercise group compared with the control group. CONCLUSIONS: Preoperative exercise training decreased short-term postoperative complications in patients with non-small cell lung cancer.

Desipramine enhances the stability of atherosclerotic plaque in rabbits monitored with molecular imaging.

Acid sphingomyelinase (ASM) promotes atherogenesis and acute cardiovascular events. We previously demonstrated ASM inhibitor desipramine attenuated oxidized-LDL-induced macrophage apoptosis in vitro. Here, we aim to determine whether ASM-mediated apoptosis in plaque improves stability in vivo. In this study, rabbits with abdominal aorta balloon injury and a 12-week high-cholesterol diet (HCD) were used to simulate an atherosclerotic plaque model. Atherosclerotic rabbits received oral administration of saline (Control group), atorvastatin (Ator group), or desipramine (DES group). ASM activity and ceramide level were measured by ultra-performance liquid chromatography (UPLC). Plaque morphology was assessed by histochemistry and immunohistochemistry. Apoptosis was evaluated by SPECT/CT imaging of 99mTc-duramycin uptake and TUNEL. We found that increasing ASM activity and ceramide level in atherosclerotic rabbits was abated by additional atorvastatin and desipramine treatment. Meanwhile, the DES and Ator groups were similar in plaque stability, with smaller plaque size, areas of macrophages, higher smooth muscle cell content, and decreased apoptosis and matrix metalloproteinase (MMP) activities relative to the Control group. 99mTc-duramycin uptake of rabbit aorta was significantly higher in Control than in the Normal group, while it was reduced by desipramine and atorvastatin administration. Moreover, the uptake of 99mTc-duramycin positively correlated with apoptotic cell number, macrophage infiltration, and plaque instability. The present study demonstrated that desipramine exerted plaque-stabilizing effects partially by suppressing apoptosis and MMP activity in a rabbit model. And 99mTc-duramycin SPECT/CT imaging allowed noninvasively monitoring of atherosclerotic disease and evaluation of anti-atherosclerotic therapy.

Intermittent fasting activates macrophage migration inhibitory factor and alleviates high-fat diet-induced nonalcoholic fatty liver disease.

Switching to normal diet (ND) is the regular therapy for high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD). Intermittent fasting (IF) is a unique treatment which may exhibits better therapeutic efficacy. Thus, we aim to investigate the therapeutic effects of these treatments and exploring the mechanisms. In the present study, NAFLD mouse model was induced by a 10-week HFD. Thereafter, mice adopted continued HFD, ND, or IF for the next 12 weeks. Finally, the liver was then harvested to assess lipid deposition, lipid metabolism, apoptosis, and autophagy, while blood was collected to determine blood glucose and insulin. The results showed that IF and ND treatment improved lipid deposition and metabolic disorder of NAFLD mice; the increasing body weight, liver weight, and HOMA-IR index of HFD mice were also alleviated by IF and ND. Furthermore, IF and ND treatment activated the macrophage migration inhibitory factor (MIF)/AMPK pathway and regulated its downstream autophagy and apoptosis. However, the efficacy of IF was better than ND. Both IF and ND activates MIF signaling and alleviate the lipotoxicity of NAFLD while IF therapy is more effective than ND. The different MIF up-regulation might be the underlying mechanism of why IF benefits more than ND.

Exercise prevents fatal stress-induced myocardial injury in obese mice.

Introduction: This study aimed to explore whether aerobic exercise (AE) can prevent fatal stress-induced myocardial injury. Methods: Thirty C57BL/6J mice were divided into either a normal diet, high-fat diet, or high-fat diet plus AE (n=10 per group). The AE protocol consisted of eight weeks of swimming. At the end of the diet and AE interventions, the mice were stimulated with fatal stress caused by exhaustive exercise (forced weight-loaded swimming until exhaustion), after which cardiac function was evaluated using echocardiography, myocardial ultrastructure was examined using transmission electron microscopy, and myocardial apoptosis was assessed using western blotting and TUNEL. Mitophagy, mitochondrial biogenesis and dynamics, and activation of the macrophage migration inhibitor factor (MIF)/AMP-activated protein kinase (AMPK) pathway were evaluated using quantitative PCR and western blotting. Obesity phenotypes were assessed once per week. Results: AE reversed high-fat diet-induced obesity as evidenced by reductions in body weight and visceral fat compared to obese mice without AE. Obesity exacerbated fatal stress-induced myocardial damage, as demonstrated by impaired left ventricular ejection fraction and myocardial structure. The apoptotic rate was also elevated upon fatal stress, and AE ameliorated this damage. Obesity suppressed mitophagy, mitochondrial fission and fusion, and mitochondrial biogenesis, and these effects were accompanied by suppression of the MIF/AMPK pathway in the myocardium of mice subjected to fatal stress. AE alleviated or reversed these effects. Conclusion: This study provides evidence that AE ameliorated fatal stress-induced myocardial injury in obese mice. The cardioprotective effect of AE in obese mice might be attributed to improved mitochondrial quality.

The long-term impact of the COVID-19 pandemic on physical fitness in young adults: a historical control study.

The strength of evidence regarding long-term changes to fitness resulting from the coronavirus disease 2019 (COVID-19) lockdowns is deficient. This two-site retrospective study aimed to investigate the long-term changes in physical fitness among young adults a year after the onset of the pandemic using a robust historical control. University freshmen who underwent physical fitness tests in 2019 and completed a follow-up in 2020 (study group) were included. The primary focus was to compare the current cohort with a historical control group who completed the same tests a year prior (2018). A total of 5376 individuals were recruited, of which 2239 were in the study group. Compared with the control, the study group exhibited a decrease in anaerobic fitness, with an overall difference of -0.84 (95% confidence interval [CI], [-1.33 to -0.36]); declines in aerobic fitness, with a difference of -2.25 [-3.92 to -0.57] for males and -4.28 [-4.97 to -3.59] for females; a reduced explosive fitness (-2.68 [-3.24 to -2.12]); and a decreased upper-body strength in females (-1.52 [-2.16 to -0.87]). The fitness of young adults has been considerably compromised by COVID-19 lockdowns, highlighting the importance of promoting physical activity to prevent long-term health implications.

A Self-Sustaining Antioxidant Strategy for Effective Treatment of Myocardial Infarction.

Myocardial infarction (MI) is the leading cause of death worldwide and can lead to the loss of cardiac function and heart failure. Reactive oxygen species (ROS) play a key role in the pathological progression of MI. The levels and effects of ROS are significantly different in three unique pathological stages of MI, and most antioxidants cannot make corresponding adjustments to eliminate ROS, which leads to a great compromise to treat MI with antioxidants. Herein, an innovative self-sustaining antioxidant strategy is developed to treat MI with self-sustaining selenium-embedded nanoparticles (SSSe NPs). SSSe NPs possess unique self-sustaining antioxidant effects at different pathological stages of MI. This strategy of on-demand ROS elimination during different pathological stages demonstrated excellent MI treatment efficacy and effectively reversed heart failure to normal heart function. The therapeutic mechanism of SSSe NPs is intensively investigated through a series of experiments and mainly involved five critical aspects of myocardial repair: protecting mitochondria, reducing cardiomyocyte apoptosis and ferroptosis, reducing inflammation and fibrosis, and promoting angiogenesis. This strategy not only provides a promising treatment option for MI but also offers inspiration for other ischemic diseases.

Trimetazidine and exercise offer analogous improvements to the skeletal muscle insulin resistance of mice through Nrf2 signaling.

INTRODUCTION: Insulin resistance (IR) plays a key role in the pathogenesis and clinical course of patients with multiple metabolic diseases and diabetes. This study aimed to explore the effect of trimetazidine (TMZ) on skeletal muscle IR in mice fed a high-fat diet (HFD) and explore the possible underlying mechanism. RESEARCH DESIGN AND METHODS: In vivo, a HFD mouse IR model was adopted and TMZ and exercise were used to intervene. Postintervention the following were determined: blood levels of glucose and insulin, homeostasis model assessment of IR index, expression of skeletal muscle insulin signaling-related proteins phosphorylated insulin receptor substrate 1 (p-IRS1/IRS1) and phosphorylated protein kinase B (p-AKT/AKT), nuclear factor erythroid 2 related factor 2 (Nrf2) signaling pathway, and oxidative stress. In vitro, a palmitate-treated C2C12 myotube IR model was constructed. Cellular glucose uptake, p-IRS1/IRS1, and p-AKT/AKT were determined, and reactive oxygen species (ROS) production was analyzed based on treatments with specific small interfering RNA of Nrf2 with or without TMZ. Western blot was used to obtain the protein expression level and ROS production by functional analysis kits. RESULTS: In vivo, TMZ and exercise decreased the blood glucose and insulin levels and homeostasis model assessment of IR index, increased skeletal muscle insulin signaling-related protein ratios of p-IRS1/IRS1 and p-AKT/AKT, and both interventions activated Nrf2 signaling and reduced oxidative stress production in HFD mice. In vitro, TMZ reduced the oxidative stress reaction, increased the ratios of p-AKT/AKT and p-IRS1/IRS1, and attenuated the insulin stimulation of PA-induced glucose uptake. However, in the absence of Nrf2, TMZ failed to resist the effects of IR. CONCLUSIONS: This study showed that TMZ, like exercise, brought about marked improvements to HFD-induced skeletal muscle IR through TMZ, a common pathway with exercise in the form of Nrf2, regulating oxidative stress. We provide new evidence to support the use of TMZ for diabetes treatment.

Rhodiola pre-conditioning reduces exhaustive exercise-induced myocardial injury of insulin resistant mice.

Myocardial injury reduction and recovery under acute cardiac stress are adversely impacted by insulin resistance (IR). We previously demonstrated that Rhodiola improved cardiac anti-stress capacity in mice. Thus, this study focuses on the preventive efficacy of Rhodiola on exhaustive exercise (EE)-induced myocardial injury of IR mice. An 8-week high-fat diet (HFD) model of IR mice was established. Rhodiola was administrated by garaging. After the 8-week intervention, half of the mice performed EE to simulate acute cardiac stress, and determine myocardial injury; The remaining mice were sacrificed following fasting to assess metabolic disorder. We found myocardial injury induced by EE in IR mice was worse and was alleviated by Rhodiola pre-conditioning. Further, the nuclear factor erythroid 2-related factor 2 (Nrf2)-related antioxidant system was impaired by HFD, while mitochondrial dynamic fusion and fission were activated by HFD as a physiological protective compensation. The Rhodiola administration rescued Nrf2 impairment and further facilitated mitochondrial fusion and fission. All these results indicate that Rhodiola is a potential treatment for the prevention of cardiac events in type 2 diabetes mellitus and metabolic syndrome patients, and the Nrf2-related antioxidant activity and mitochondrial dynamics are the proposed mechanisms.

Exercise intensity and energy expenditure of a multicomponent home-based training program: Xiangya hospital circuit training (X-CircuiT).

Introduction: Our previous studies showed that Xiangya Hospital Circuit Training (X-CircuiT) effectively improved physical fitness and reversed pre-frailty in community-dwelling older adults. This study aimed to explore the generalizability and applicability of X-CircuiT in different aged populations in the context of exercise intensity and energy expenditure. Methods: We prospectively recruited 72 community-dwelling sedentary adults, twelve adults divided into 6 age groups ranging from 20 to 80 years old and separated by decades. Cardiopulmonary exercise testing was performed to determine peak heart rate (HRpeak). An individual HR-oxygen consumption regression equation was fit for each participant, and then a session of remote heart rate monitored X-CircuiT was performed. Exercise intensity (%HRpeak) and energy expenditure of X-CircuiT among the six age groups were assessed. Further sub-analysis was conducted by dividing the participants by peak metabolic equivalent (MET) values, <5 METs, 5-7 METs, and more than 7METs to explore the relationship between maximum exercise capacity and exercise intensity of X-CircuiT. Results: The average %HRpeak of X-CircuiT for subjects in the 20-29, 30-39, 40-49, 50-59, 60-69, and 70-80 age groups were 54 ± 6, 59 ± 8, 60 ± 8, 62 ± 5, 66 ± 10, and 67 ± 13, respectively (p = 0.008); and the average energy expenditure was 121.9 ± 26.5, 123.3 ± 33.8, 129.2 ± 40.9, 130.9 ± 31.8, 146.8 ± 29.0, and 125.0 ± 28.4 kcal, respectively. The average %HRpeak for the warm-up, aerobic, acupoint patting, resistance, and stretching stages in overall subjects was 61 ± 9, 70 ± 10, 70 ± 10, 63 ± 9, and 57 ± 9, respectively. Furthermore, when subjects were divided by peak METs, it was found that the lower the peak METs, the greater the value of the relative exercise intensity indicators. The aerobic and acupoint stages of X-CircuiT could illicit a response of high intensity for those with peak METs <5, moderate intensity in those with peak METs of 5-7, and low-intensity for those with peak METs of more than 7. Conclusion: Xiangya Hospital Circuit Training followed the principle of low-intensity warm-up and medium-intensity training with multicomponent exercise training. It is classified as a moderate-intensity exercise for sedentary middle-aged and older adults, or those with a maximum exercise capacity of 5-7 METs, and is classified as a low-intensity exercise for young people.

Exercise inhibits JNK pathway activation and lipotoxicity via macrophage migration inhibitory factor in nonalcoholic fatty liver disease.

The macrophage migration inhibitory factor (MIF) expressed in hepatocytes can limit steatosis during obesity. Lipotoxicity in nonalcoholic fatty liver disease is mediated in part by the activation of the stress kinase JNK, but whether MIF modulates JNK in lipotoxicity is unknown. In this study, we investigated the role of MIF in regulating JNK activation and high-fat fostered liver lipotoxicity during simultaneous exercise treatment. Fifteen mice were equally divided into three groups: normal diet, high-fat diet, and high-fat and exercise groups. High-fat feeding for extended periods elicited evident hyperlipemia, liver steatosis, and cell apoptosis in mice, with inhibited MIF and activated downstream MAPK kinase 4 phosphorylation and JNK. These effects were then reversed following prescribed swimming exercise, indicating that the advent of exercise could prevent liver lipotoxicity induced by lipid overload and might correlate to the action of modulating MIF and its downstream JNK pathway. Similar detrimental effects of lipotoxicity were observed in in vitro HepG2 cells palmitic acid treatment. Suppressed JNK reduced the hepatocyte lipotoxicity by regulating the BCL family, and the excess JNK activation could also be attenuated through MIF supplementation or exacerbated by MIF siRNA administration. The results found suggest that exercise reduces lipotoxicity and inhibits JNK activation by modulating endogenous hepatic MIF in NAFLD. These findings have clinical implications for the prevention and intervention of patients with immoderate diet evoked NAFLD.

Rhodiola activates macrophage migration inhibitory factor to alleviate non-alcoholic fatty liver disease.

AIMS: Rhodiola was found to be a potential treatment for nonalcoholic fatty liver disease (NAFLD). The macrophage migration inhibitory factor (MIF)-regulated lipophagy and lipid metabolism might be the therapeutic targets of Rhodiola. MAIN METHODS: A 16-week high-fat diet (HFD) was used to simulate a NAFLD mouse model. Rhodiola extract or normal saline were administrated to mice. Blood was collected to assess blood glucose and insulin, and livers were harvested to assess lipid accumulation and metabolism. In cell experiments, the active ingredient of Rhodiola, salidroside, and recombinant MIF protein (rMIF) were used to treat palmitate (PA)-incubated HepG2 cells, with MIF-siRNA or NC-siRNA transfection. Then, the level of lipophagy and lipid metabolism was examined. KEY FINDINGS: Rhodiola improved lipid accumulation and metabolism disorder of HFD mice. The oil red O staining of the liver showed that increased lipid droplets in the NAFLD liver could be relieved by Rhodiola; Rhodiola also alleviated the increasing body weight, liver weight, and HOMA-IR index of HFD mice. Results in cell experiments were consistent: salidroside relieved the lipid droplet accumulation and triglyceride release in PA cells, as well as reduced lipophagosome and lipid metabolism disorder in PA cells. However, all these effects of salidroside were partially blocked by MIF-siRNA transfection. SIGNIFICANCE: Rhodiola reduces lipid accumulation in the liver of NAFLD by facilitating the MIF pathway and the downstream lipophagy and lipid metabolism. MIF may be an endogenous regulator of liver lipophagy and lipid metabolism and a potential therapeutic target for NAFLD.

Prophylactic exercise-derived circulating exosomal miR-125a-5p promotes endogenous revascularization after hindlimb ischemia by targeting endothelin converting enzyme 1.

Background: Prophylactic exercise improves clinical outcomes in patients experiencing severe ischemic diseases. Previous studies have shown that exercise could alter the amount or content of circulating exosomes. However, little is known about the role of precursory exercise-derived circulating exosomes (Exe-Exo) in ischemic diseases. We therefore aimed to explore the function and mechanism of Exe-Exo in endogenous revascularization and perfusion recovery in peripheral arterial disease. Methods and Results: We first determined that 4 weeks of precursory treadmill exercise improved perfusion recovery on days 7, 14 and 21 after unilateral femoral artery ligation (FAL) but had no effect immediately after ligation. Then, local muscle delivery of Exe-Exo promotes arteriogenesis, angiogenesis and perfusion recovery, which could be abolished by GW4869, a well-recognized pharmacological agent inhibiting exosome release. This suggests that Exe-Exo mediated exercise-induced revascularization. In vitro, Exe-Exo enhanced endothelial cell proliferation, migration and tube formation. In addition, we identified miR-125a-5p as a novel exerkine through exosomal miRNA sequencing and RT-qPCR validation. Inhibition of miR-125a-5p abrogated the beneficial effects of Exe-Exo both in vivo and in vitro. Mechanistically, these exercise-afforded benefits were attributed to the exosomal miR-125a-5p downregulation of ECE1 expression and the subsequent activation of the AKT/eNOS downstream signaling pathway. Specifically, skeletal muscle may be a major tissue source of exercise-induced exosomal miR-125a-5p via fluorescence in situ hybridization. Conclusions: Endogenous circulating exosomal miR-125a-5p promotes exercise-induced revascularization via targeting ECE1 and activating AKT/eNOS downstream signaling pathway. Identify exosomal miR-125a-5p as a novel exerkine, and highlight its potential therapeutic role in the prevention and treatment of peripheral arterial disease.

Trimetazidine and exercise provide comparable improvements to high fat diet-induced muscle dysfunction through enhancement of mitochondrial quality control.

Obesity induces skeletal muscle dysfunction. The pathogenesis of which appears to substantially involve mitochondrial dysfunction, arising from impaired quality control. Exercise is a major therapeutic strategy against muscle dysfunction. Trimetazidine, a partial inhibitor of lipid oxidation, has been proposed as a metabolic modulator for several cardiovascular pathologies. However, the effects of Trimetazidine on regulating skeletal muscle function are largely unknown. Our present study used cell culture and obese mice models to test a novel hypothesis that Trimetazidine could improve muscle atrophy with similar results to exercise. In C2C12 cells, high palmitic acid-induced atrophy and mitochondrial dysfunction, which could be reversed by the treatment of Trimetazidine. In our animal models, with high-fat diet-induced obesity associated with skeletal muscle atrophy, Trimetazidine prevented muscle dysfunction, corrected metabolic abnormalities, and improved mitochondrial quality control and mitochondrial functions similarly to exercise. Thus, our study suggests that Trimetazidine successfully mimics exercise to enhance mitochondrial quality control leading to improved high-fat diet-induced muscle dysfunction.

The Treatment of Rhodiola Mimics Exercise to Resist High-Fat Diet-Induced Muscle Dysfunction via Sirtuin1-Dependent Mechanisms.

Muscle dysfunction is a complication of high-fat diet (HFD)-induced obesity that could be prevented by exercise, but patients did not get enough therapeutic efficacy from exercise due to multiple reasons. To explore alternative or supplementary approaches to prevent or treat muscle dysfunction in individuals with obesity, we investigated the effects of Rhodiola on muscle dysfunction as exercise pills. SIRT1 might suppress atrogenes expression and improve mitochondrial quality control, which could be a therapeutic target stimulated by exercise and Rhodiola, but further mechanisms remain unclear. We verified the lipid metabolism disorders and skeletal muscle dysfunction in HFD feeding mice. Moreover, exercise and Rhodiola were used to intervene mice with a HFD. Our results showed that exercise and Rhodiola prevented muscle atrophy and dysfunction in obese mice and activating the SIRT1 pathway, while atrogenes were suppressed and mitochondrial quality control was improved. EX-527, SIRT1 inhibitor, was used to validate the essential role of SIRT1 in salidroside benefit. Results of cell culture experiment showed that salidroside alleviated high palmitate-induced atrophy and mitochondrial quality control impairments, but these improvements of salidroside were inhibited by EX-527 in C2C12 myotubes. Overall, Rhodiola mimics exercise that activates SIRT1 signaling leading to improvement of HFD-induced muscle dysfunction.

Exercise improves lipid droplet metabolism disorder through activation of AMPK-mediated lipophagy in NAFLD.

AIM: To emphasize the mechanism of the effect of exercise on lipid droplet (LD) metabolism disorder in nonalcoholic fatty liver disease (NAFLD). MAIN METHODS: C57BL/6J mice were randomly divided into three groups: The first group was fed with a normal diet (CON), the second group was fed a high-fat diet (HF), and finally group with a high-fat diet intervention and swim training (HF-EX). The total intervention period was 16 weeks. RT-PCR and Western blot were performed to evaluate the effect of exercise on LDs metabolism and the AMPK pathway. Histopathological examinations and immunofluorescence were performed to evaluate the lipid deposition and lipophagy in the liver. KEY FINDINGS: Exercise reduced liver steatosis and insulin resistance along with the stimulation of AMPK/SIRT1 signaling and downstream regulation of lipid metabolism. In addition, exercise increased the expression of autophagy marker and colocalization of LC3 and LAMP1 with LDs. SIGNIFICANCE: Exercise stimulated AMPK/SIRT1 and activated lipophagy in NAFLD. Enhancing lipophagy may be one of the key mechanisms of regulation and resolution of NAFLD by exercise.

Weight gain in Chinese youth during a 4-month COVID-19 lockdown: a retrospective observational study.

OBJECTIVES: To observe the weight change in Chinese youth during a 4-month COVID-19 lockdown, and the association between weight change and mental health, physical activity and sedentary time changes, and dietary habits. DESIGN: A retrospective observational study. SETTINGS: Two universities located in Zhejiang and Hunan provinces, China. PARTICIPANTS: This study enrolled 12 889 college students whose body weight was measured before the lockdown (1 December 2019-20 January 2020) at the two universities, and reported their weight measured at home or community after the end of the lockdown (1-23 May 2020) via an online follow-up questionnaire. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the weight change in Chinese youth during a 4-month lockdown resulting from the COVID-19 pandemic. The secondary outcomes were the relationships of weight change to COVID-19-related stress, depression, anxiety, physical activity and sedentary time changes, and dietary habits. RESULTS: Participants' ages ranged from 17 to 27 years (M=19, SD=1) with 80.2% identified as female. The average absolute and relative changes in body weight were 2.6 (95% CI 2.0 to 3.2)) kg and 4.2% (95% CI 4.0% to 4.3%) for men, and 2.1 (1.9 to 2.4) kg and 4.2% (95% CI 3.9% to 4.4%) for women. An increase in overweight and obese individuals according to Asian cut-off points as a demographic percentage by 4.5% and 2.7% and 4.8% and 3.4% in men and women, respectively (P<0.001), was observed. Weight gain was significantly associated with increased sedentary time and an increase in COVID-19-related stress and depression score. CONCLUSION: The present study's results suggest that the risk of weight gain in Chinese youth during the lockdown increased and that strategies to decrease sedentary time and improve mental health may be warranted to mitigate weight gain during and after the COVID-19 pandemic.

Phosphoproteomics identifies potential downstream targets of the integrin α2ß1 inhibitor BTT-3033 in prostate stromal cells.

BACKGROUND: Integrin α2ß1 inhibitor BTT-3033 (1-(4-fluorophenyl)-N-methyl-N-[4[[(phenylamino)carbonyl]amino]phenyl]-1H-pyrazole-4-sulfonamide) was recently reported to inhibit neurogenic and thromboxane A2-induced human prostate smooth muscle contraction, and thus represents a target with a different inhibition spectrum than that of α1-blockers in benign prostate hyperplasia (BPH) treatments. Clarifying the underlying mechanisms of the inhibition effects will provide insights into the role of integrin α2ß1 in prostate contraction and enable new intracellular targets for smooth muscle contraction to be explored. METHODS: ProteomeHD was used to predict and enrich the top co-regulated proteins of integrin α2 (ITGA2). A phosphoproteomic analysis was conducted on human prostate stromal cells (WPMY-1) treated with 1 or 10 µM of BTT-3033 or solvent for controls. A clustering analysis was conducted to identify the intracellular targets that were inhibited in a dose-dependent manner. Gene ontology (GO) and annotation enrichments were conducted to examine any functional alterations and identify possible downstream targets. A Kinase-substrate enrichment analysis (KSEA) was conducted to identify kinases-substrate relationships. RESULTS: Enrichments of the actin cytoskeleton and guanosine triphosphatases (GTPases) signaling were predicted from the co-regulated proteins with ITGA2. LIM domain kinases, including LIM domain and actin-binding 1 (LIMA1), zyxin (ZYX), and thyroid receptor-interacting protein 6 (TRIP6), which are functionally associated with focal adhesions and the cytoskeleton, were present in the clusters with dose-dependent phosphorylation inhibition pattern. 15 substrates were dose-dependently inhibited according to the KSEA, including polo-like kinase 1 (PLK1), and GTPases signaling proteins, such as disheveled segment polarity protein 2 (DVL2). CONCLUSIONS: In this study, we proposed that the mechanisms underlying the contractile and proliferative effects of integrin α2ß1 are the LIM domain kinases, including the ZYX family, and substrates, including PLK1 and DVL2.