The validity and reliability of the My Jump 2 app for measuring vertical stiffness in male college players.

Background: Vertical stiffness (Kvert) can be used to evaluate sports performance and injury risk in players. The My Jump 2 smartphone application (App), is increasingly being used by researchers, coaches, and players in the competitive sports field. We aimed to analyze the reliability and concurrent validity of the My Jump 2 app for measuring Kvert in male college players. Methods: Twenty male college players (10 soccer players, 10 basketball players; age, 20.2 ± 1.3 years old; weight, 76.4 ± 6.0 kg; height, 178.3 ± 4.7 cm) volunteered to take part in this study. Three drop jumps were performed by participants from 30 cm to 40 cm on a force platform and retested after three days. All the jumps were recorded by both the Force platform and the My Jump 2 app. Data obtained from the above two devices were compared using the paired t tests, intraclass correlation coefficient (ICC), coefficient of variation (CV), Pearson product moment correlation coefficient (r), Bland-Altman plots, and one-way regression. Results: There was almost perfect agreement between measurement instruments for the Kvert value (ICC > 0.972, 95% CI = 0.954-0.992, P < 0.01). Almost perfect agreement was observed between evaluators (ICC > 0.989, 95% CI = 0.981-0.997, P < 0.05). Also, the My Jump 2 app showed excellent intra-rater reliability in all participants (ICC = 1.000, 95% CI = 1.000-1.000, P < 0.001). The My Jump 2 showed good variability when measuring Kvert at T1 30 cm (CV = 5.4%), T1 40 cm (CV = 6.7%), T2 30 cm (CV = 5.0%), and T2 40 cm (CV = 10.3%). The test-retest reliability of My Jump 2 was moderate to good at 30 cm (ICC = 0.708, 95% CI = 0.509-0.827); however, it was lower to moderate at 40 cm (ICC = 0.445, 95% CI = 0.222-0.625). Very large correlations were observed between the force platform and the My Jump 2 for Kvert (r > 0.9655, P < 0.001). Conclusion: The My Jump 2 smartphone application showed excellent reliability and intra-rater consistency in measuring Kvert in male college players. While demonstrating excellent intra-rater consistency and strong agreement with force platform measurements, it showed slightly lower reliability at higher jump heights. Overall, the My Jump 2 app is a valid tool for evaluating Kvert in college players with careful consideration of its limitations, particularly at higher jump heights.

Exploring exercise-driven exerkines: unraveling the regulation of metabolism and inflammation.

Exercise has many beneficial effects that provide health and metabolic benefits. Signaling molecules are released from organs and tissues in response to exercise stimuli and are widely termed exerkines, which exert influence on a multitude of intricate multi-tissue processes, such as muscle, adipose tissue, pancreas, liver, cardiovascular tissue, kidney, and bone. For the metabolic effect, exerkines regulate the metabolic homeostasis of organisms by increasing glucose uptake and improving fat synthesis. For the anti-inflammatory effect, exerkines positively influence various chronic inflammation-related diseases, such as type 2 diabetes and atherosclerosis. This review highlights the prospective contribution of exerkines in regulating metabolism, augmenting the anti-inflammatory effects, and providing additional advantages associated with exercise. Moreover, a comprehensive overview and analysis of recent advancements are provided in this review, in addition to predicting future applications used as a potential biomarker or therapeutic target to benefit patients with chronic diseases.

Connection of pre-competition anxiety with gut microbiota and metabolites in wrestlers with varying sports performances based on brain-gut axis theory.

OBJECTIVE: The purpose of this study is to investigate the connection of pre-competition anxiety with gut microbiota and metabolites in wrestlers with different sports performances. METHODS: One week prior to a national competition, 12 wrestlers completed anxiety questionnaires. Faecal and urine samples were collected for the analysis of gut microbiota and metabolites through the high-throughput sequencing of the 16 S rRNA gene in conjunction with untargeted metabolomics technology. The subjects were divided into two groups, namely, achievement (CP) and no-achievement (CnP) wrestlers, on the basis of whether or not their performances placed them in the top 16 at the competition. The relationship amongst the variations in gut microbiota, metabolites, and anxiety indicators was analyzed. RESULTS: (1) The CP group exhibited significantly higher levels of "state self-confidence," "self-confidence," and "somatic state anxiety" than the CnP group. Conversely, the CP group displayed lower levels of "individual failure anxiety" and "sports competition anxiety" than the CnP group. (2) The gut microbiota in the CP group was more diverse and abundant than that in the CnP group. Pre-competition anxiety was linked to Oscillospiraceae UCG_005, Paraprevotella, Ruminococcaceae and TM7x. (3) The functions of differential metabolites in faeces and urine of the CP/CnP group were mainly enriched in caffeine metabolism, lipopolysaccharide biosynthesis and VEGF and mTOR signaling pathways. Common differential metabolites in feces and urine were significantly associated with multiple anxiety indicators. CONCLUSIONS: Wrestlers with different sports performance have different pre-competition anxiety states, gut microbiota distribution and abundance and differential metabolites in faeces and urine. A certain correlation exists between these psychological and physiological indicators.

Trimethylamine N-Oxide Improves Exercise Performance by Reducing Oxidative Stress through Activation of the Nrf2 Signaling Pathway.

Trimethylamine N-oxide (TMAO) has attracted interest because of its association with cardiovascular disease and diabetes, and evidence for the beneficial effects of TMAO is accumulating. This study investigates the role of TMAO in improving exercise performance and elucidates the underlying molecular mechanisms. Using C2C12 cells, we established an oxidative stress model and administered TMAO treatment. Our results indicate that TMAO significantly protects myoblasts from oxidative stress-induced damage by increasing the expression of Nrf2, heme oxygenase-1 (HO-1), NAD(P)H dehydrogenase (NQO1), and catalase (CAT). In particular, suppression of Nrf2 resulted in a loss of the protective effects of TMAO and a significant decrease in the expression levels of Nrf2, HO-1, and NQO1. In addition, we evaluated the effects of TMAO in an exhaustive swimming test in mice. TMAO treatment significantly prolonged swimming endurance, increased glutathione and taurine levels, enhanced glutathione peroxidase activity, and increased the expression of Nrf2 and its downstream antioxidant genes, including HO-1, NQO1, and CAT, in skeletal muscle. These findings underscore the potential of TMAO to counteract exercise-induced oxidative stress. This research provides new insights into the ability of TMAO to alleviate exercise-induced oxidative stress via the Nrf2 signaling pathway, providing a valuable framework for the development of sports nutrition supplements aimed at mitigating oxidative stress.

MCC950 Ameliorates Diabetic Muscle Atrophy in Mice by Inhibition of Pyroptosis and Its Synergistic Effect with Aerobic Exercise.

Diabetic muscle atrophy is an inflammation-related complication of type-2 diabetes mellitus (T2DM). Even though regular exercise prevents further deterioration of atrophic status, there is no effective mediator available for treatment and the underlying cellular mechanisms are less explored. In this study, we investigated the therapeutic potential of MCC950, a specific, small-molecule inhibitor of NLRP3, to treat pyroptosis and diabetic muscle atrophy in mice. Furthermore, we used MCC950 to intervene in the protective effects of aerobic exercise against muscle atrophy in diabetic mice. Blood and gastrocnemius muscle (GAS) samples were collected after 12 weeks of intervention and the atrophic state was assessed. We initially corroborated a diabetic muscle atrophy phenotype in db/db mice (D) by comparison with control m/m mice (W) by examining parameters such as fasting blood glucose (D vs. W: 24.47 ± 0.45 mmol L-1 vs. 4.26 ± 0.6 mmol L-1, p < 0.05), grip strength (D vs. W: 166.87 ± 15.19 g vs. 191.76 ± 14.13 g, p < 0.05), exercise time (D vs. W: 1082.38 ± 104.67 s vs. 1716 ± 168.55 s, p < 0.05) and exercise speed to exhaustion (D vs. W: 24.25 ± 2.12 m min-1 vs. 34.75 ± 2.66 m min-1, p < 0.05), GAS wet weight (D vs. W: 0.07 ± 0.01 g vs. 0.13 ± 0.01 g, p < 0.05), the ratio of GAS wet weight to body weight (D vs. W: 0.18 ± 0.01% vs. 0.54 ± 0.02%, p < 0.05), and muscle fiber cross-sectional area (FCSA) (D vs. W: 1875 ± 368.19 µm2 vs. 2747.83 ± 406.44 µm2, p < 0.05). We found that both MCC950 (10 mg kg-1) treatment and exercise improved the atrophic parameters that had deteriorated in the db/db mice, inhibited serum inflammatory markers and significantly attenuated pyroptosis in atrophic GAS. In addition, a combined MCC950 treatment with exercise (DEI) exhibited a further improvement in glucose uptake capacity and muscle performance. This combined treatment also improved the FCSA of GAS muscle indicated by Laminin immunofluorescence compared to the group with the inhibitor treatment alone (DI) (DEI vs. DI: 2597 ± 310.97 vs. 1974.67 ± 326.15 µm2, p < 0.05) or exercise only (DE) (DEI vs. DE: 2597 ± 310.97 vs. 2006.33 ± 263.468 µm2, p < 0.05). Intriguingly, the combination of MCC950 treatment and exercise significantly reduced NLRP3-mediated inflammatory factors such as cleaved-Caspase-1, GSDMD-N and prevented apoptosis and pyroptosis in atrophic GAS. These findings for the first time demonstrate that targeting NLRP3-mediated pyroptosis with MCC950 improves diabetic muscle homeostasis and muscle function. We also report that inhibiting pyroptosis by MCC950 can enhance the beneficial effects of aerobic exercise on diabetic muscle atrophy. Since T2DM and muscle atrophy are age-related diseases, the young mice used in the current study do not seem to fully reflect the characteristics of diabetic muscle atrophy. Considering the fragile nature of db/db mice and for the complete implementation of the exercise intervention, we used relatively young db/db mice and the atrophic state in the mice was thoroughly confirmed. Taken together, the current study comprehensively investigated the therapeutic effect of NLRP3-mediated pyroptosis inhibited by MCC950 on diabetic muscle mass, strength and exercise performance, as well as the synergistic effects of MCC950 and exercise intervention, therefore providing a novel strategy for the treatment of the disease.

Aerobic exercise improves BKCa channel-mediated vasodilation in diabetic vascular smooth muscle via AMPK/Nrf2/HO-1 pathway.

AIMS: This study aims to investigate the effect of aerobic exercise training on BKCa channel in diabetic vascular smooth muscle and explore the underlying mechanism. METHODS: Control m/m mice and diabetic db/db mice were randomly assigned to sedentary groups (W and D) and exercise training groups (WE and DE). Mice in exercise groups underwent training sessions lasting for 12 weeks, with a speed of 12 m/min for 60 min, five times per week. The thoracic aorta was extracted isolated and examined for measurement of vascular structure, global levels of reactive oxygen species (ROS), vasodilation, and protein expression. Rat thoracic aorta vascular smooth muscle cells (USMCs) were cultured, and siRNA transfection was conducted to detect whether AMPK contributed to the regulation. ROS level and protein expression were measured. RESULTS: Compared with control mice, diabetic mice had a larger vascular medium thickness, impaired BKCa-mediated vasodilation, a higher level of ROS, and a lower expression of BKCa α, BKCa ß1, Nrf2, p-Nrf2, p-Nrf2/Nrf2, HO-1, and p-AMPK/AMPK. Exercise training increased the expression of BKCa α, Nrf2, p-Nrf2, p-Nrf2/Nrf2, HO-1, and p-AMPK/AMPK. AMPK deletion led to lower ROS levels and expression of BKCa α, ß1, Nrf2, and HO-1 in USMCs cultured in high glucose conditions. CONCLUSIONS: BKCa channel protein expression reduction in VSMCs contributes to vasodilation and vascular remodeling dysfunction in diabetes mellitus. Aerobic exercise can promote the expression of BKCa channel and improve BKCa-mediated vascular dysfunction in diabetic VSMCs through AMPK/Nrf2/HO-1 signaling pathway.

Effects of resistance training on alleviating hypoxia-induced muscle atrophy: Focus on acetylation of FoxO1.

This study aims to explore the role of FoxO1 and its acetylation in the alleviation of hypoxia-induced muscle atrophy by resistance training. Forty male Sprague-Dawley rats were randomly divided into four groups: normoxic control group (C), normoxic resistance training group (R), hypoxic control group (H) and hypoxic resistance training group (HR). Rats in R and HR groups were trained on an incremental weight-bearing ladder every other day, while those in H and HR groups were kept in an environment containing 12.4% O2 . After 4 weeks, muscles were collected for analysis. Differentiated L6 myoblasts were analysed in vitro after hypoxia exposure and plasmids transfection (alteration in FoxO1 acetylation). The lean body mass loss, wet weight and fibre cross-sectional area of extensor digitorum longus of rats were decreased after 4 weeks hypoxia, and the adverse reactions above was reversed by resistance training. At the same time, the increase in hypoxia-induced autophagy was suppressed, which was accompanied by a decrease in the expression of nuclear FoxO1 and cytoplasmic Ac-FoxO1 by resistance training. The L6 myotube diameter increased and the expression of autophagic proteins were inhibited under hypoxia via intervening by FoxO1 deacetylation. Overall, resistance training alleviates hypoxia-induced muscle atrophy by inhibiting nuclear FoxO1 and cytoplasmic Ac-FoxO1-mediated autophagy.

Exploring exercise-driven inhibition of pyroptosis: novel insights into treating diabetes mellitus and its complications.

Diabetes mellitus (DM) and its complications are important, worldwide public health issues, exerting detrimental effects on human health and diminishing both quality of life and lifespan. Pyroptosis, as a new form of programmed cell death, plays a critical role in DM and its complications. Exercise has been shown to be an effective treatment for improving insulin sensitivity or preventing DM. However, the molecular mechanisms underlying the effects of exercise on pyroptosis-related diseases remain elusive. In this review, we provided a comprehensive elucidation of the molecular mechanisms underlying pyroptosis and the potential mechanism of exercise in the treatment of DM and its complications through the modulation of anti-pyroptosis-associated inflammasome pathways. Based on the existing evidence, further investigation into the mechanisms by which exercise inhibits pyroptosis through the regulation of inflammasome pathways holds promising potential for expanding preventive and therapeutic strategies for DM and facilitating the development of novel therapeutic interventions.

Weight bearing training alleviates muscle atrophy and pyroptosis of middle-aged rats.

Background: Age-related muscle atrophy and adipose accumulation begin to occur in young and middle-aged individuals, and exercise at an early age improves body composition. Pyroptosis may play an essential role in age-related low-grade inflammation. This study aimed to explore the alleviation of muscle atrophy by weight-bearing training with increasing age via inhibition of pyroptosis. Methods: Ninety 8-month-old male SD rats were randomly divided into three groups: (1) normal baseline group (N group, n = 10), sacrificed after adaptive feeding; control group (C group, n = 40); and weight-bearing running group (R group, n = 40). Blood samples, adipose tissue (AT), and extensor digitorum longus (EDL) were collected after 8, 16, 24, and 32-weeks intervention. Results: The body weight, muscle mass, fat mass, plasma lipid, AT wet weight, adipocyte cross-sectional area (CSA), and apoptosis rates of AT and EDL were increased, while the muscle mass, wet weight, and fiber CSA of EDL were decreased by aging, which were reversed by exercise. Weight-bearing training promoted protein synthesis in EDL, inhibited protein degradation in EDL, and expression of pyroptotic key proteins in EDL and AT in rats. Conclusion: Weight-bearing training improves body composition and alleviates age-related muscle atrophy in rats, and its mechanism may be related to the inhibition of pyroptosis in the EDL and AT and the improvement of muscle protein metabolism.

Aerobic exercise reduced the amount of CHRONO bound to BMAL1 and ameliorated glucose metabolic dysfunction in skeletal muscle of high-fat diet-fed mice.

AIMS: The purpose of this study was to investigate the effects of aerobic exercise on the CHRONO-BMAL1 pathway and glucose metabolism in skeletal muscle of high-fat diet (HFD)-fed mice. MAIN METHODS: Male C57BL/6J mice were randomly allocated into four groups: normal chow diet with control (NCD + CON), NCD with exercise (NCD + EXE), HFD with control (HFD + CON) and HFD with exercise (HFD + EXE). The NCD and HFD groups were respectively fed a diet of 10 % and 60 % kilocalories from fat for 12 weeks. During the dietary intervention, EXE groups were subjected to 70 % VO2max intensity of treadmill exercise six times per week for 12 weeks. Body weight, energy intake, fat weight, serum lipid profiles, systemic glucose homeostasis, the amount of CHRONO bound to BMAL1, the enzymatic activity, mRNA and protein expression involved in glucose metabolism of skeletal muscle were measured. KEY FINDINGS: The results showed that the 12-week HFD feeding without exercise induced weight gain, serum dyslipidemia and insulin resistance. Furthermore, HFD increased the amount of CHRONO bound to BMAL1 and repressed the glucose metabolism in skeletal muscle. However, aerobic exercise prevented weight gain, serum dyslipidemia and systemic insulin resistance in the HFD-fed mice. Meanwhile, aerobic exercise also decreased the amount of CHRONO bound to BMAL1 and increased the glucose uptake, glucose oxidation and glycogenesis in skeletal muscle of the HFD-fed mice. SIGNIFICANCE: These data suggested that aerobic exercise could counterbalance CHRONO interacted with BMAL1 and prevent glucose metabolism dysfunction of skeletal muscle, and finally maintain whole-body insulin sensitivity in the HFD-fed mice.

FGF21: A Sharp Weapon in the Process of Exercise to Improve NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is a pathological syndrome characterized by excessive fat deposition in hepatocytes. A sedentary lifestyle is a major risk factor for NAFLD, and regular exercise is considered a cornerstone of NAFLD treatment independent of weight loss. Even low-intensity activity could have beneficial effects on NAFLD. Fibroblast growth factor 21 (FGF21), a cytokine mainly secreted by the liver, improves glucolipid metabolism, reduces inflammation and oxidative stress, increases insulin sensitivity, and acts on multiple organs through autocrine, paracrine, and endocrine actions. Both clinical trials and animal experiments have shown a high correlation between liver fat content and circulating blood FGF21 levels, and abnormal FGF21 signaling appears to be an important mechanism for the development of NAFLD. FGF21 is an exerkine that responds to exercise; therefore, it may be a key target in exercise to improve NAFLD. This review provides an overview of NAFLD and its pathogenesis, and summarizes the effects of exercise intervention on NAFLD, as well as the role of FGF21 in NAFLD. Emphasis is placed on possible mechanisms for improving NAFLD by targeting FGF21 during exercise.

Regular Tennis Exercise May Improve the Vascular Endothelial Function in Postmenopausal Women: The Influence of Hemodynamics.

Physical inactivity plays a role in the incidence of cardiovascular disease (CVD). Although the current guidelines for physical activity, such as the prescription of exercise, seek to combat CVD, attaining the recommended targets remains challenging. Tennis exercise has been proven to have a unique advantage in reducing the mortality of CVD, but little is known about the influence of playing tennis on impaired vascular endothelial function (VEF), which initiates CVD. Thus, this study aimed to investigate whether regular tennis participation could protect the VEF better than merely meeting the physical activity recommended by the current guidelines. A cross-sectional design was performed based on a sample of 38 healthy postmenopausal women who were matched for physical activity, of which 17 subjects had long-term tennis experience and 21 age-matched subjects regularly exercised but did not play tennis. The cardiovascular function and the body composition of all subjects were measured. We used cluster analysis to assess the overall health status. The modeling results showed that the tennis players performed better in terms of VEF than the nonplayers (10.55 ± 0.58 vs. 8.69 ± 0.52, p < 0.01, R2ad = 0.367), while the wall shear stress positively correlated with VEF (r = 0.505, p < 0.05), after controlling for age and physical activity levels. Regular tennis exercise may be a protective factor for VEF, and further study should be performed to research the role of hemodynamics in tennis exercise.

Effects of Six Weeks of Hypoxia Exposure on Hepatic Fatty Acid Metabolism in ApoE Knockout Mice Fed a High-Fat Diet.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease with a characteristic of abnormal lipid metabolism. In the present study, we employed apolipoprotein E knockout (ApoE KO) mice to investigate the effects of hypoxia exposure on hepatic fatty acid metabolism and to test whether a high-fat diet (HFD) would suppress the beneficial effect caused by hypoxia treatment. ApoE KO mice were fed a HFD for 12 weeks, and then were forwarded into a six-week experiment with four groups: HFD + normoxia, normal diet (ND) + normoxia, HFD + hypoxia exposure (HE), and ND + HE. The C57BL/6J wild type (WT) mice were fed a ND for 18 weeks as the baseline control. The hypoxia exposure was performed in daytime with normobaric hypoxia (11.2% oxygen, 1 h per time, three times per week). Body weight, food and energy intake, plasma lipid profiles, hepatic lipid contents, plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and molecular/biochemical makers and regulators of the fatty acid synthesis and oxidation in the liver were measured at the end of interventions. Six weeks of hypoxia exposure decreased plasma triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) contents but did not change hepatic TG and non-esterified fatty acid (NEFA) levels in ApoE KO mice fed a HFD or ND. Furthermore, hypoxia exposure decreased the mRNA expression of Fasn, Scd1, and Srebp-1c significantly in the HFD + HE group compared with those in the HFD + normoxia group; after replacing a HFD with a ND, hypoxia treatment achieved more significant changes in the measured variables. In addition, the protein expression of HIF-1α was increased only in the ND + HE group but not in the HFD + HE group. Even though hypoxia exposure did not affect hepatic TG and NEFA levels, at the genetic level, the intervention had significant effects on hepatic metabolic indices of fatty acid synthesis, especially in the ND + HE group, while HFD suppressed the beneficial effect of hypoxia on hepatic lipid metabolism in male ApoE KO mice. The dietary intervention of shifting HFD to ND could be more effective in reducing hepatic lipid accumulation than hypoxia intervention.

Effect of Exercise Training on Arterial Stiffness in Overweight or Obese Populations.

The purpose was to analyze the effects of exercise training (ET) on arterial stiffness in all-age overweight or obese individuals. Sixty-one trials were included with ET improving flow-mediated dilation (FMD), pulse wave velocity (PWV), and intima-media thickness (IMT). In the subgroup analysis: (i) ET improved FMD in overweight or obese children and adolescents with a large effect size (SMD=0.83, 95% CI 0.42-1.25). PWV was decreased after ET regardless of age. IMT was decreased by ET in participants younger than 60, (ii) ET improved FMD, PWV, and IMT in participants whose BMI were smaller than 30 kg/m2, but ET only improved PWV of participants whose BMI were larger than 30 kg/m2. (iii) AE improved FMD, PWV, and IMT. High-intensity interval training (HIIT) decreased IMT. (iv) The increase of FMD only happened when training duration was longer than eight weeks. However, ET decreased PWV when the training duration was no longer than 12 weeks. IMT was decreased when the training duration was longer than eight weeks. ET instigated an improvement in endothelial function and arterial stiffness in overweight or obese populations, but depending on the different characteristics of exercise intervention and participants' demographics.

HnRNP D activates production of HPV16 E1 and E6 mRNAs by promoting intron retention.

Human papillomavirus type 16 (HPV16) E1 and E6 proteins are produced from mRNAs with retained introns, but it has been unclear how these mRNAs are generated. Here, we report that hnRNP D act as a splicing inhibitor of HPV16 E1/E2- and E6/E7-mRNAs thereby generating intron-containing E1- and E6-mRNAs, respectively. N- and C-termini of hnRNP D contributed to HPV16 mRNA splicing control differently. HnRNP D interacted with the components of splicing machinery and with HPV16 RNA to exert its inhibitory function. As a result, the cytoplasmic levels of intron-retained HPV16 mRNAs were increased in the presence of hnRNP D. Association of hnRNP D with HPV16 mRNAs in the cytoplasm was observed, and this may correlate with unexpected inhibition of HPV16 E1- and E6-mRNA translation. Notably, hnRNP D40 interacted with HPV16 mRNAs in an HPV16-driven tonsillar cancer cell line and in HPV16-immortalized human keratinocytes. Furthermore, knockdown of hnRNP D in HPV16-driven cervical cancer cells enhanced production of the HPV16 E7 oncoprotein. Our results suggest that hnRNP D plays significant roles in the regulation of HPV gene expression and HPV-associated cancer development.

Identification of heterogenous nuclear ribonucleoproteins (hnRNPs) and serine- and arginine-rich (SR) proteins that induce human papillomavirus type 16 late gene expression and alter L1 mRNA splicing.

We have determined the effect of seven serine- and arginine-rich (SR) proteins and 15 heterogenous nuclear ribonucleoproteins (hnRNPs) on human papillomavirus type 16 (HPV16) late gene expression. Of the seven SR proteins analyzed here, SRSF1, SRSF3, and SRSF9 induced HPV16 late gene expression, and five of the SR proteins affected HPV16 L1 mRNA splicing. Of the 15 hnRNP proteins analyzed here, hnRNP A2, hnRNP F, and hnRNP H efficiently induced HPV16 late gene expression, and all of the hnRNPs affected HPV16 L1 mRNA levels or mRNA splicing. Thus, the majority of SR proteins and hnRNPs have the potential to regulate HPV16 L1 mRNA splicing. Strict control of the expression of the immunogenic L1 and L2 capsid proteins may contribute to the ability of HPV16 to cause persistence.

High-Intensity Interval Training and Moderate-Intensity Continuous Training Attenuate Oxidative Damage and Promote Myokine Response in the Skeletal Muscle of ApoE KO Mice on High-Fat Diet.

The purpose of this study was to investigate the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on the skeletal muscle in Apolipoprotein E knockout (ApoE KO) and wild-type (WT) C57BL/6J mice. ApoE KO mice fed with a high-fat diet were randomly allocated into: Control group without exercise (ApoE-/- CON), HIIT group (ApoE-/- HIIT), and MICT group (ApoE-/- MICT). Exercise endurance, blood lipid profile, muscle antioxidative capacity, and myokine production were measured after six weeks of interventions. ApoE-/- CON mice exhibited hyperlipidemia and increased oxidative stress, compared to the WT mice. HIIT and MICT reduced blood lipid levels, ROS production, and protein carbonyl content in the skeletal muscle, while it enhanced the GSH generation and potently promoted mRNA expression of genes involved in the production of irisin and BAIBA. Moreover, ApoE-/- HIIT mice had significantly lower plasma HDL-C content, mRNA expression of MyHC-IIx and Vegfa165 in EDL, and ROS level; but remarkably higher mRNA expression of Hadha in the skeletal muscle than those of ApoE-/- MICT mice. These results demonstrated that both exercise programs were effective for the ApoE KO mice by attenuating the oxidative damage and promoting the myokines response and production. In particular, HIIT was more beneficial to reduce the ROS level in the skeletal muscle.

Aerobic exercise promotes the functions of brown adipose tissue in obese mice via a mechanism involving COX2 in the VEGF signaling pathway.

BACKGROUND: High-fat diet (HFD)-induced obesity causes immune cells to infiltrate adipose tissue, leading to chronic inflammation and metabolic syndrome. Brown adipose tissue (BAT) can dissipate the energy produced by lipid oxidation as heat, thereby counteracting obesity. Aerobic exercise activates BAT, but the specific underlying mechanism is still unclear. METHODS: Male C57BL/6 J mice were divided into a normal diet control group (NC group) and HFD group (H group). After becoming obese, the animals in the H group were subdivided into a control group (HC group) and an exercise group (HE group, with treadmill training). After 4 weeks, the mRNA profile of BAT was determined, and then differentially expressed key genes and pathways were verified in vitro. RESULTS: Relative to the NC group, the genes upregulated in the HC group coded mainly for proteins involved in immune system progression and inflammatory and immune responses, while the downregulated genes regulated lipid metabolism and oxidation-reduction. Relative to the HC group, the genes upregulated in the HE group coded for glycolipid metabolism, while those that were downregulated were involved in cell death and apoptosis. VEGF and other signaling pathways were enhanced by aerobic exercise. Interaction analysis revealed that the gene encoding cyclooxygenase 2 (COX2) of the VEGF signaling pathway is central to this process, which was verified by a sympathetic activator (isoprenaline hydrochloride) and COX2 inhibitor (NS-398). CONCLUSIONS: In mice with HFD-induced obesity, four weeks of aerobic exercise elevated BAT mass and increased the expression of genes related to glycolipid metabolism and anti-inflammatory processes. Several pathways are involved, with COX2 in the VEGF signaling pathway playing a key role.

Heterogeneous Nuclear Ribonucleoprotein A1 (hnRNP A1) and hnRNP A2 Inhibit Splicing to Human Papillomavirus 16 Splice Site SA409 through a UAG-Containing Sequence in the E7 Coding Region.

Human papillomavirus 16 (HPV16) 5'-splice site SD226 and 3'-splice site SA409 are required for production of the HPV16 E7 mRNAs, whereas unspliced mRNAs produce E6 mRNAs. The E6 and E7 proteins are essential in the HPV16 replication cycle but are also the major HPV16 proteins required for induction and maintenance of malignancy caused by HPV16 infection. Thus, a balanced expression of unspliced and spliced mRNAs is required for production of sufficient quantities of E6 and E7 proteins under physiological and pathophysiological conditions. If splicing becomes too efficient, the levels of unspliced E6 mRNAs will decrease below a threshold level that is no longer able to produce E6 protein quantities high enough to significantly reduce p53 protein levels. Similarly, if splicing becomes too inefficient, the levels of spliced E7 mRNAs will decrease below a threshold level that is no longer able to produce E7 protein quantities high enough to significantly reduce pRb protein levels. To determine how splicing between SD226 and SA409 is regulated, we have investigated how SA409 is controlled by the cellular proteins hnRNP A1 and hnRNP A2, two proteins that have been shown previously to control HPV16 gene expression. We found that hnRNP A1 and A2 interacted directly and specifically with a C-less RNA element located between HPV16 nucleotide positions 594 and 604 downstream of SA409. Overexpression of hnRNP A1 inhibited SA409 and promoted production of unspliced E6 mRNAs at the expense of the E7 mRNAs, whereas overexpression of hnRNP A2 inhibited SA409 to redirect splicing to SA742, a downstream 3'-splice site that is used for generation of HPV16 E6̂E7, E1, and E4 mRNAs. Thus, high levels of either hnRNP A1 or hnRNP A2 inhibited production of the promitotic HPV16 E7 protein. We show that the hnRNP A1 and A2 proteins control the relative levels of the HPV16 unspliced and spliced HPV16 E6 and E7 mRNAs and function as inhibitors of HPV16 E7 expression.IMPORTANCE Human papillomavirus type 16 (HPV16) belongs to the high-risk-group of HPVs and is causing a variety of anogenital cancers and head and neck cancer. The two HPV16 oncoproteins E6 and E7 prevent apoptosis and promote mitosis and are essential for completion of the HPV16 life cycle and for transformation of the infected cell and maintenance of malignancy. E6 and E7 are produced from two mRNAs that are generated in a mutually exclusive manner by alternative splicing. While E6 protein is made from the unspliced mRNA, E7 is made from the spliced version of the same pre-mRNA. Since sufficient quantities of both E6 and E7 are required for malignant transformation, this intricate arrangement of gene expression renders E6 and E7 expression vulnerable to external interference. Since antiviral drugs to HPV16 are not available, a detailed knowledge of the regulation of HPV16 E6 and E7 mRNA splicing may uncover novel targets for therapy.

Efficient production of HPV16 E2 protein from HPV16 late mRNAs spliced from SD880 to SA2709.

Human papillomaviruses (HPVs) produce a large number of alternatively spliced mRNAs, including a number of differently spliced mRNAs with the potential to produce E2 protein. To identify the alternatively spliced HPV16 mRNA with the highest ability to produce E2 protein, we have generated E2 cDNA expression plasmids representing the most common, alternatively spliced E2 mRNAs, and assessed their translational potential. Our results revealed that an mRNA initiated at the HPV16 late promoter p670 and spliced from the HPV16 5'-splice site SD880 to the HPV16 3'-splice site SA2709, located immediately upstream of the E2 ATG, produced higher levels of E2 than any of the other alternatively spliced, E2-encoding mRNAs. Utilization of a known, alternative 3'-splice site located upstream of the E2 ATG named SA2582, generated mRNAs with lower ability to produce E2 than mRNAs spliced to SA2709. Finally, analysis of HPV16 mRNA splicing demonstrated that SA2709 was more efficiently spliced to the upstream 5'-splice site SD880 than to the upstream 5'-splice site SD226. In conclusion, the HPV16 mRNA with the greatest ability to produce E2 protein is generated from the HPV16 late promoter and is spliced between HPV16 5'-splice site SD880 and HPV16 3'-splice site SA2709.