bims-exemet Biomed News
on Exercise metabolism
Issue of 2021‒02‒28
seventeen papers selected by
Javier Botella Ruiz
Victoria University

  1. J Appl Physiol (1985). 2021 Feb 25.
      There are limited and equivocal data regarding potential fiber type-specific differences in the human skeletal muscle response to sprint interval training (SIT), including how this compares to moderate-intensity continuous training (MICT). We examined mixed muscle and fiber type-specific responses to a single session (study 1) and 12 wk (study 2) of MICT and SIT using Western blotting. MICT consisted of 45 min of cycling at ~70% of maximal heart rate and SIT involved 3 x 20-sec 'all-out' sprints interspersed with 2 min of recovery. Changes in signaling proteins involved in mitochondrial biogenesis in mixed muscle and pooled fiber samples were similar after acute MICT and SIT. This included increases in the ratios of phosphorylated to total acetyl CoA carboxylase and p38 mitogen activated protein kinase protein content (main effects, p<0.05). Following training, mitochondrial content markers including the protein content of cytochrome c oxidase subunit IV and NADH:ubiquinone oxidoreductase subunit A9 were increased similarly in mixed muscle and type IIa fibers (main effects, p<0.05). In contrast, only MICT increased these markers of mitochondrial content in type I fibers (interactions, p<0.05). MICT and SIT also similarly increased the content of mitochondrial fusion proteins optic atrophy 1 (OPA1) and mitofusin 2 in mixed muscle, and OPA1 in pooled fibre samples (main effects, p<0.05). In summary, acute MICT and SIT elicited similar fiber type-specific responses of signaling proteins involved in mitochondrial biogenesis, whereas 12 wk of training revealed differential responses of mitochondrial content markers in type I but not type IIa fibers.
    Keywords:  Western blotting; aerobic exercise; mitochondria; single fiber
  2. Eur J Prev Cardiol. 2019 Nov 13. pii: 2047487319887828. [Epub ahead of print]
      OBJECTIVES: The present study compares the effect of high-intensity interval training (HIIT; 18 min) and moderate-intensity continuous training (MIT; 1 h) on reverse cholesterol transport (RCT) elements in obese subjects.METHODS: Thirty adult male rats were induced high-fat diet (HFD) for 12 weeks. After four weeks, the rats were randomly divided into three groups while simultaneously continuing the HFD for the remaining eight weeks. Group specificities were HFD-control, HFD-MIT and HFD-HIIT. The rats were sacrificed 48 h after the last training session and the samples were collected. Analysis of variance and Pearson's correlation test were used for the statistical analyses (significance level: p ≤ 0.05).
    RESULTS: The results showed that both HIIT and MIT improved heart ABCA1, ABCG1, ABCG4, ABCG5, ABCG8, LXR-α and PPARγ gene expression as well as plasma Apo A1, LCAT, lipids and lipoproteins (p ≤ 0.05). Moreover, higher cardiac ABCA1, ABCG1, ABCG4, ABCG5, ABCG8 and PPARγ expression and plasma high-density lipoprotein cholesterol (p ≤ 0.05) concentrations were found in the HFD-HIIT group compared with the HFD-MIT group.
    CONCLUSION: HIIT may have more cardioprotective effects than MIT against atherosclerosis, along with saving time, as supported by the changes observed in the main factors involved in the RCT process.
    Keywords:  Cardioprotection; high-fat diet; lipoproteins; obesity; reverse cholesterol transport (RCT)
  3. J Physiol Biochem. 2021 Feb 26.
      The unfolded protein response (UPR) plays a pivotal role in some exercise training-induced physiological adaptation. Our aim was to evaluate the changes in the protein kinase R-like endoplasmic reticulum kinase (PERK) arm of the UPR and hypertrophy signaling pathway following 8 weeks of resistance training and creatine (Cr) supplementation in rats. Thirty-two adult male Wistar rats (8 weeks old) were randomly divided into 4 groups of 8: untrained + placebo (UN+P), resistance training + placebo (RT+P), untrained + Cr (UN+Cr), and resistance training + Cr (RT+Cr). Trained animals were submitted to the ladder-climbing exercise training 5 days per week for a total of 8 weeks. Cr supplementation groups received creatine diluted with 1.5 ml of 5% dextrose orally. The flexor hallucis longus (FHL) muscle was extracted 48 h after the last training session and used for western blotting. After training period, the RT+Cr and RT+P groups presented a significant increase in phosphorylated and phosphorylated/total ratio hypertrophy indices, phosphorylated and phosphorylated/total ratio PERK pathway proteins, and other downstream proteins of the PERK cascade compared with their untrained counterparts (P < 0.05). The increase in hypertrophy indices were higher but PERK pathway proteins were lower in the RT-Cr group than in the RT+P group (P < 0.05). There was no significant difference between the untrained groups (P > 0.05). Our study suggests that resistance training in addition to Cr supplementation modifies PERK pathway response and improves skeletal muscle hypertrophy.
    Keywords:  Creatine; Ladder-climbing training; Muscle mass; PERK pathway; UPR
  4. Front Cell Dev Biol. 2021 ;9 625680
      Acute exercise increases the amount of circulating inflammatory cells and cytokines to maintain physiological homeostasis. However, it remains unclear how physical training regulates exercise-induced inflammation and performance. Here, we demonstrate that acute high intensity exercise promotes an inflammatory profile characterized by increased blood IL-6 levels, neutrophil migratory capacity, and leukocyte recruitment to skeletal muscle vessels. Moreover, we found that physical training amplified leukocyte-endothelial cell interaction induced by acute exercise in skeletal muscle vessels and diminished exercise-induced inflammation in skeletal muscle tissue. Furthermore, we verified that disruption of the gp-91 subunit of NADPH-oxidase inhibited exercise-induced leukocyte recruitment on skeletal muscle after training with enhanced exercise time until fatigue. In conclusion, the training was related to physical improvement and immune adaptations. Moreover, reactive oxygen species (ROS) could be related to mechanisms to limit aerobic performance and its absence decreases the inflammatory response elicited by exercise after training.
    Keywords:  exercise; muscular inflammation; neutrophil; oxidative stress; physical training
  5. Eur J Nutr. 2021 Feb 26.
      PURPOSE: Exercise plays an important role in preventing and treating postprandial dysmetabolism. We investigated the postprandial metabolic responses to a standard lunch when a session of aerobic exercise is performed in the early postprandial phase or divided between the pre- and postprandial period.METHODS: Nine healthy volunteers consumed a standardised mixed lunch and rested for the following 3 h (Con) or performed 40 min of cycling at 65% V̇O2max after lunch (CPPEx), or two 20-min sessions, one before (SplitEx1) and the other after lunch (SplitEx2), at the same intensity.
    RESULTS: At 1-h post-lunch, a significant reduction (P < 0.001) in glycaemia was observed for CPPEx (- 25 ± 10%) and SplitEx (- 34 ± 7%) compared to Con. Yet, a post-exercise rebound lessened the exercise effect on the glycaemic area under the curve (AUC) at 2 and 3 h. At 1 h, a significant reduction (P < 0.009) in plasma insulin (SplitEx - 53 ± 31%; CCPEx - 48 ± 20%) and C-peptide (SplitEx - 57 ± 20%; CCPEx - 47 ± 24%) was observed compared to Con. Glucose-dependent insulinotropic polypeptide (GIP) increased after the meal, without differences between conditions. Compared with SplitEx1, cortisol response was attenuated during SplitEx2 and CPPEx. At 3 hours, triglyceride AUC was significantly higher (P = 0.039) in SplitEx compared to Con (+ 19 ± 8%).
    CONCLUSION: Forty minutes of postprandial exercise or 20 min of pre- and postprandial exercise are both effective at attenuating the glycaemic and insulinaemic response to a mixed lunch, while a higher lipaemia was found in the pre- and postprandrial exercise condition.
    Keywords:  Exercise timing; Glucose control; Lipidemia; Physical activity; Postprandial events
  6. Life Sci. 2021 Feb 21. pii: S0024-3205(21)00250-2. [Epub ahead of print] 119265
      The objective of the current study was examining early and late (3, 24 h) responses to acute, chronic swimming exercise as muscle damage and regeneration in gastrocnemius-soleus muscle complexes. We also aimed to reveal the signaling pathways involved. 8-12 weeks old mice were grouped as control, exercise. Exercising groups were firstly divided into two as acute and chronic, later every group was again divided in terms of time (3, 24 h) passed from the last exercise session until exsanguination. Acute exercise groups swam 30 min, while chronic swimming groups exercised 30 min/day, 5 days/week, 6 weeks. Histological investigations were performed to determine muscle damage and regeneration. Whole-genome expression analysis was applied to total RNA samples. Microarray data was confirmed by quantitative real-time PCR. Exercising mice muscle revealed enhanced damage, leukocyte infiltration. Increments in acute and chronic 3 h groups were statistically significant. Car3, Neb, Obscn, Ttn, Igfbp5, Igfbp7, Gsk3β, and Usp2 were down-regulated in muscles of swimming mice. The exercise-induced signaling pathways involved in muscle damage and regeneration were drawn. Our findings demonstrate that swimming induces muscle damage. Samples were obtained at 3 and 24 h following exercise, this time duration seems not sufficient for the development of myofibrillogenesis.
    Keywords:  Myofibrillogenesis; Skeletal muscle damage; Swimming exercise; Whole-genome expression analysis
  7. Front Physiol. 2020 ;11 570170
      Cachexia is a multifactorial inflammatory syndrome with high prevalence in cancer patients. It is characterized by a metabolic chaos culminating in drastic reduction in body weight, mainly due to skeletal muscle and fat depletion. Currently, there is not a standard intervention for cachexia, but it is believed that a dynamic approach should be applied early in the course of the disease to maintain or slow the loss of physical function. The present review sought to explain the different clinical and experimental applications of different models of exercise and their contribution to a better prognosis of the disease. Here the advances in knowledge about the application of physical training in experimental models are elucidated, tests that contribute substantially to elucidate the cellular and biochemical mechanisms of exercise in different ways, as well as clinical trials that present not only the impacts of exercise in front cachexia but also the challenges of its application in clinical practice.
    Keywords:  aerobic; muscle atrophy; muscle wasting; neoplasms; resistance; systemic inflammation; therapeutic exercise; tumor
  8. Exp Physiol. 2021 Feb 24.
      NEW FINDING: What is the central question of this study? How does moderate-intensity aerobic exercise affect the behavior of purinergic enzymes in sedentary, overweight and physically active subjects? What is the relationship between purinergic and inflammatory responses triggered by exercise? What is the main finding and its importance? Moderate-intensity aerobic exercise modifies the activity of purinergic enzymes and the levels of nucleotides and nucleosides. These results are similar in subjects with different biological characteristics. 5'-nucleotidase activity and adenosine levels are associated with inflammatory responses. This study suggests that a purinergic pathway is related to the inflammatory responses triggered by exercise.ABSTRACT: Purinergic signaling is a mechanism of extracellular communication that modulate events related to exercise, such as inflammation and coagulation. Herein, we evaluated the effects of acute moderate-intensity exercise on the activities of purinergic enzymes and plasma levels of adenine nucleotides in individuals with distinct metabolic characteristics. We analyzed the relationship between purinergic parameters, inflammatory responses and cardiometabolic markers. Twenty-four healthy males were assigned to three groups: normal weight sedentary (n = 8), overweight sedentary (n = 8) and normal weight physically active (n = 8). The volunteers performed an acute session of moderate-intensity aerobic exercise on a treadmill at 70% of V̇O2peak ; blood samples were drawn at baseline, immediately post-exercise and at 1h post-exercise. Immediately post-exercise, all subjects showed increases in ATP, ADP, AMP and p-Nph-5'-TMP hydrolysis, while AMP hydrolysis remained increased at 1h after exercise. High-performance liquid chromatography analysis demonstrated lower levels of ATP and ADP at post- and 1h post-exercise in all groups. Conversely, adenosine and inosine levels increased at post-exercise, but only adenosine remained augmented at 1h after exercise in all groups. With regard to inflammatory responses, the exercise protocol increased TNF-α and IL-8 concentrations in all subjects, but only TNF-α remained elevated at 1h after exercise. Significant correlations were found between the activity of 5'-NT, adenosine levels, V̇O2peak , triglyceride, TNF-α and IL-8 levels. Our findings suggest a purinergic signaling pathway that participates, at least partially, in the inflammatory responses triggered by acute moderate-intensity exercise. The response of soluble nucleotidases to acute moderate exercise appears to be similar between subjects of different biological profiles. This article is protected by copyright. All rights reserved.
    Keywords:  5’-nucleotidase; NTPDases; exercise; inflammation; nucleotidases
  9. J Cell Physiol. 2021 Feb 21.
      Aerobic exercise increases M2 AChR, which thus improves cardiac function in cardiovascular disease (CVD) rats. This study aimed to determine whether aerobic exercise could ameliorate pressure overload-induced heart hypertrophy through M2 AChR, and to elucidate the underlying mechanisms of action. Mice were used to establish the myocardial hypertrophy model by transverse aortic constriction (TAC), and subjected to 2, 4, and 8 weeks of moderate-intensity aerobic exercise and choline intervention (14 mg/kg/day). Our results showed that 4 and 8 weeks of exercise and choline intervention reduced excessive mitochondrial fission and autophagy of myocardial mitochondria, thereby improving the ultrastructure and function of mitochondria after TAC. Moreover, 8-week exercise and choline intervention have enhanced parasympathetic function and promoted the expression of M2 AChR. In addition, 8-week exercise and choline intervention also inhibited the protein expression of myocardial MFN2, PERK/eIF2α/ATF4, and NLRP3/caspase-1/IL-1β signaling pathways, thereby effectively reducing mitochondrial fusion, endoplasmic reticulum stress, and inflammation. Taken together, these data suggest that pressure overload led to cardiac hypertrophy, cardiac dysfunction, and decreased parasympathetic function in cardiac tissues. Aerobic exercise attenuated cardiac dysfunction by modulating the expression of proteins involved in mitochondrial quality control, and induced endoplasmic reticulum stress and inflammation, thereby reducing cardiac hypertrophy and improving cardiac function in impaired heart tissues following TAC, which was likely mediated by M2 AChR activation.
    Keywords:  M2AChR; aerobic exercise; choline; endoplasmic reticulum stress; inflammation; mitochondrial quality control; myocardial hypertrophy
  10. Sci Rep. 2021 Feb 25. 11(1): 4639
      It is believed that neutrophils extracellular traps (NETs) formation is responsible for the increase in cf DNA after exercise. Since T1DM is accompanied by enhanced NETs generation, we compared exercise-induced increase in cf DNA in 14 men with T1DM and 11 healthy controls and analyzed its association with exercise load. Subjects performed a treadmill run to exhaustion at speed corresponding to 70% of their personal VO2max. Blood was collected before and just after exercise for determination of plasma cf nuclear and mitochondrial DNA (cf n-DNA, cf mt-DNA) by real-time PCR, blood cell count and metabolic markers. Exercise resulted in the increase in median cf n-DNA from 3.9 ng/mL to 21.0 ng/mL in T1DM group and from 3.3 ng/mL to 28.9 ng/mL in controls. Median exercise-induced increment (∆) in cf n-DNA did not differ significantly in both groups (17.8 ng/mL vs. 22.1 ng/mL, p = 0.23), but this variable correlated with run distance (r = 0.66), Δ neutrophils (r = 0.86), Δ creatinine (r = 0.65) and Δ creatine kinase (r = 0.77) only in controls. Pre- and post-exercise cf mt-DNA were not significantly different within and between groups. These suggest low usefulness of Δ cf n-DNA as a marker of exercise intensity in T1DM men.
  11. Mol Biol Rep. 2021 Feb 24.
      The research literature suggests that different training modalities cause various patterns in training-induced genes expression. This study aimed to investigate the effects of moderate intensity continuous training (MICT) and isocaloric high intensity interval training (HIIT) on gene expression of monocarboxylate transporter 1 (MCT1) and 4 (MCT4), Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and hypoxia inducible factor-1α (HIF-1α) in soleus and extensor digitorum longus (EDL) skeletal muscles of rats. Thirty male Sprague-Dawley rats were divided into 3 groups of control, MICT, and HIIT. Training protocols were performed according to the principle of overload for 8 weeks and 5 sessions per week. Then, the soleus and EDL muscles were extracted and the expression levels were analyzed using the real time PCR method. In the MICT group, only the EDL HIF-1α mRNA level was significantly higher than that of the control group (p < 0.05). In the HIIT group, however, mRNA levels of MCT4, PGC-1α, and HIF-1α in both muscles were significantly higher than those of the control group (p < 0.05). The comparison between the two training methods demonstrated that the gene expression levels of soleus and EDL MCT4, soleus PGC-1α, and soleus HIF-1α were significantly higher in the HIIT group compared to the MICT group (p < 0.05). There were also significant positive correlations between all mRNA levels of HIF-1α and corresponding mRNA levels of MCT4 (p < 0.05). HIIT caused greater positive responses in the gene expression of MCT4, PGC-1α, and HIF-1α compared to MICT.
    Keywords:  High intensity interval training; Hypoxia inducible factor-1α; Moderate intensity continuous training; Monocarboxylate transporters; Peroxisome proliferator-activated receptor γ coactivator-1α; Training modalities
  12. Biomed Res Int. 2021 ;2021 1947928
      Exercise-induced benefits are being increasingly recognized in promoting health and preventing diseases. However, initial adaption to exercise response can have different effects on cells, including an increase in the formation of oxidants and inflammatory mediators that ultimately leads to oxidative stress, but this scenario depends on the exercise type and intensity and training status of the individual. Therefore, we aimed to understand the effect of different types of exercise on oxidative stress. Indeed, exercise-induced minimum oxidative stress is required for regulating signaling pathways. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, a search for relevant articles was carried out on PubMed/Medline, ISI Web of Science, and Google Scholar using a broad range of synonyms such as oxidants, reactive oxygen species (ROS), oxidative stress, exercise, physical training, aerobic exercise, and strength exercise until 2019. This study selected a total of 18 articles for assessing the oxidative damage using various parameters such as malondialdehyde (MDA), protein carbonyl (PCO), and F1-isoprostanes and enzymatic antioxidants. We observed that any type of exercise can increase the oxidative damage in an exercise type and intensity manner. Further, the training status of the individual and specific oxidative damage marker plays a crucial role in predicting earlier oxidative damage in the exercise condition. However, some of the studies that we included for review did not perform follow-up evaluations. Therefore, follow-up programs using larger numbers need to be performed to confirm our findings.
  13. Int J Sport Nutr Exerc Metab. 2021 Feb 23. pii: ijsnem.2020-0270. [Epub ahead of print] 1-8
      Cannabidiol (CBD) has proven clinical benefits in the treatment of seizures, inflammation, and pain. The recent legalization of CBD in many countries has caused increased interest in the drug as an over-the-counter treatment for athletes looking to improve recovery. However, no data on the effects of CBD on the adaptive response to exercise in muscle are available. To address this gap, we eccentrically loaded the tibialis anterior muscle of 14 rats, injected them with a vehicle (n = 7) or 100 mg/kg CBD (n = 7), and measured markers of injury, inflammation, anabolic signaling, and autophagy 18 hr later. Pro-inflammatory signaling through nuclear factor kappa B (NF-kB) (Ser536) increased with loading in both groups; however, the effect was significantly greater (36%) in the vehicle group (p < .05). Simultaneously, anabolic signaling through ribosomal protein S6 kinase beta-1 (S6K1) (Thr389) increased after eccentric contractions in both groups with no difference between vehicle and CBD (p = .66). The ribosomal protein S6 phosphorylation (240/244) increased with stimulation (p < .001) and tended to be higher in the CBD group (p = .09). The ubiquitin-binding protein p62 levels were not modulated by stimulation (p = .6), but they were 46% greater in the CBD compared with the vehicle group (p = .01). Although liver weight did not differ between the groups (p = .99) and levels of proteins associated with stress were similar, we did observe serious side effects in one animal. In conclusion, an acute dose of CBD decreased pro-inflammatory signaling in the tibialis anterior without blunting the anabolic response to exercise in rats. Future research should determine whether these effects translate to improved recovery without altering adaptation in humans.
    Keywords:  CBD; inflammation; mTORC1; muscle; recovery
  14. Horm Mol Biol Clin Investig. 2021 Feb 08.
      OBJECTIVES: High fat diet can lead to testicular structural and functional disturbances, spermatogenesis disorders as well as infertility. So, the present investigation was proposed to clarify whether voluntary exercise could prevent high fat diet induced reproductive complications in rats through testicular stress oxidative and apoptosis.METHODS: Forty male Wistar rats were randomly divided into four groups; control (C), voluntary exercise (VE), high fat diet (HFD) and high fat diet and voluntary exercise (VE + HFD) groups. The rats in the VE and VE + HFD groups were accommodated in apart cages that had running wheels and the running distance was assessed daily for 10 weeks. In VE + HFD group, animals were fed with HFD for five weeks before commencing exercise. The sperm parameters, the expressions of testicular miR-34a gene, and P53 and SIRT1 proteins as well as testicular apoptosis were analyzed in all groups.
    RESULTS: The results indicated that voluntary exercise in VE + HFD group led to significantly increased GPX and SOD activities, SIRT1 protein expression, sperm parameters, and decreased the expression of miR34a gene and Acp53 protein, and cellular apoptosis index compared to HFD group (p<0.001 to p<0.05). The SOD and catalase activities, SIRT1 protein expression, sperm parameters in VE + HFD group were lower than of those of VE group, however, MDA content, expression of Acp53 protein, apoptosis indexes in VE + HFD group was higher than that of VE group (p<0.001 to p<0.05).
    CONCLUSION: This study revealed that voluntary exercise improved spermatogenesis, in part by decreasing the testicular oxidative stress status, apoptosis through alteration in miR-34a/SIRT1/p53 pathway.
    Keywords:  SIRT1; apoptosis; mir-34a; oxidative stress; p53; voluntary exercise
  15. Br J Sports Med. 2021 Feb 22. pii: bjsports-2020-103323. [Epub ahead of print]
      OBJECTIVES: We investigated whether high responsiveness or low responsiveness to exercise training aggregates in the same individuals across seven cardiometabolic traits.METHODS: A total of 564 adults (29.2% black, 53.7% female) from the HERITAGE family study completed a 20-week endurance training programme (at 55%-75% of participants' maximal oxygen uptake (VO2max)) with VO2max, per cent body fat, visceral adipose tissue, fasting levels of insulin, high-density lipoprotein cholesterol, small low-density lipoprotein particles and inflammatory marker GlycA measured before and after training. For each exercise response trait, we created ethnicity-specific, sex-specific and generation-specific quintiles. High responses were defined as those within the 20th percentile representing the favourable end of the response trait distribution, low responses were defined as the 20th percentile from the least favourable end, and the remaining were labelled as average responses.
    RESULTS: Only one individual had universally high or low responses for all seven cardiometabolic traits. Almost half (49%) of the cohort had at least one high response and one low response across the seven traits. About 24% had at least one high response but no low responses, 24% had one or more low responses but no high responses, and 2.5% had average responses across all traits.
    CONCLUSIONS: Interindividual variation in exercise responses was evident in all the traits we investigated, and responsiveness did not aggregate consistently in the same individuals. While adherence to an exercise prescription is known to produce health benefits, targeted risk factors may not improve.
    Keywords:  exercise physiology; exercise training
  16. Bone Res. 2021 Feb 26. 9(1): 15
      Osteoporosis (OP) is a common skeletal disease involving low bone mineral density (BMD) that often leads to fragility fracture, and its development is affected by multiple cellular pathologies and associated with marked epigenetic alterations of osteogenic genes. Proper physical exercise is beneficial for bone health and OP and reportedly possesses epigenetic modulating capacities; however, whether the protective effects of exercise on OP involve epigenetic mechanisms is unclear. Here, we report that epigenetic derepression of nuclear factor erythroid derived 2-related factor-2 (Nrf2), a master regulator of oxidative stress critically involved in the pathogenesis of OP, mediates the significant osteoprotective effects of running exercise (RE) in a mouse model of OP induced by ovariectomy. We showed that Nrf2 gene knockout (Nfe2l2-/-) ovariectomized mice displayed a worse BMD reduction than the controls, identifying Nrf2 as a critical antiosteoporotic factor. Further, femoral Nrf2 was markedly repressed with concomitant DNA methyltransferase (Dnmt) 1/Dnmt3a/Dnmt3b elevations and Nrf2 promoter hypermethylation in both patients with OP and ovariectomized mice. However, daily 1-h treadmill RE significantly corrected epigenetic alterations, recovered Nrf2 loss and improved the femur bone mass and trabecular microstructure. Consistently, RE also normalized the adverse expression of major osteogenic factors, including osteoblast/osteoclast markers, Nrf2 downstream antioxidant enzymes and proinflammatory cytokines. More importantly, the RE-conferred osteoprotective effects observed in the wild-type control mice were largely abolished in the Nfe2l2-/- mice. Thus, Nrf2 repression due to aberrant Dnmt elevation and subsequent Nrf2 promoter hypermethylation is likely an important epigenetic feature of the pathogenesis of OP, and Nrf2 derepression is essential for the antiosteoporotic effects of RE.
  17. Front Cell Dev Biol. 2021 ;9 634853
      Extracellular vesicles (EVs) have emerged as key players of intercellular communication and mediate crosstalk between tissues. Metastatic tumors release tumorigenic EVs, capable of pre-conditioning distal sites for organotropic metastasis. Growing evidence identifies muscle cell-derived EVs and myokines as potent mediators of cellular differentiation, proliferation, and metabolism. Muscle-derived EVs cargo myokines and other biological modulators like microRNAs, cytokines, chemokines, and prostaglandins hence, are likely to modulate the remodeling of niches in vital sites, such as liver and adipose tissues. Despite the scarcity of evidence to support a direct relationship between muscle-EVs and cancer metastasis, their indirect attribution to the regulation of niche remodeling and the establishment of pre-metastatic homing niches can be put forward. This hypothesis is supported by the role of muscle-derived EVs in findings gathered from other pathologies like inflammation and metabolic disorders. In this review, we present and discuss studies that evidently support the potential roles of muscle-derived EVs in the events of niche pre-conditioning and remodeling of metastatic tumor microenvironment. We highlight the potential contributions of the integrin-mediated interactions with an emerging myokine, irisin, to the regulation of EV-driven microenvironment remodeling in tumor metastasis. Further research into muscle-derived EVs and myokines in cancer progression is imperative and may hold promising contributions to advance our knowledge in the pathophysiology, progression and therapeutic management of metastatic cancers.
    Keywords:  extracellular vesicles; homing niche; integrins; irisin; muscle; myokines; tissue microenvironment; tumor metastasis