Abstract:New Findings
What is the central question of this study?Does Dnmt3a play a crucial role in regulating diabetic muscle atrophy?
What is the main finding and its importance?Muscle atrophy is one of the major long‐term complications of diabetes mellitus. However, little is known about the molecular mechanism involved. In this paper, we demonstrated that Dnmt3a overexpression effectively improves the diabetic muscle health in mice and documented the underlying mechanisms. DNMT3A might become a promising target to… Show more
“…In this study, we found that Dnmt3 (Dnmt3a and Dnmt3b), but not Dnmt1 exhibited responsive expression after CE incubation to eliminate STS-induced toxicity ( Figure 4 ). Recently, Dnmt3a was reported to improve muscle atrophy in diabetic mice by activating Akt, suggesting that Dnmt3a could provide feedback to the PI3K/Akt signaling pathway and play a role in maintaining cell survival ( Wang et al., 2020 ). Furthermore, CE-mediated recovery of CaM was impaired by 5-AZ, an inhibitor of Dnmts.…”
We previously demonstrated the antioxidant activity of Coeloglossum viride var. bracteatum extract (CE) in rat cortical neurons and in mice with chemically induced cognitive impairment. In this work, we established a staurosporine (STS)-induced toxicity model to decipher the neuroprotective mechanisms of CE. We found that CE protected cell viability and neurite integrity in STS-induced toxicity by restoring the levels of FGF2 and its associated PI3K/Akt signaling axis. LY294002, a pan-inhibitor of PI3K, antagonized the activity of CE, although its-mediated restoration of FGF2 was unaffected. In addition, CE restored levels of Bcl-2/Caspase-3, PKCα/CaM pathway, and Dnmt3a and Dnmt3b, two methyltransferases that contribute to de novo DNA methylation. The Dnmts inhibitor 5-azacytidine impaired CE-mediated restoration of Dnmt3 or CaM, as well as the transition of DNA methylation status on the Dnmt3 promoter. These results reveal potential mechanisms that could facilitate the study and application of CE as a neuroprotective agent.
“…In this study, we found that Dnmt3 (Dnmt3a and Dnmt3b), but not Dnmt1 exhibited responsive expression after CE incubation to eliminate STS-induced toxicity ( Figure 4 ). Recently, Dnmt3a was reported to improve muscle atrophy in diabetic mice by activating Akt, suggesting that Dnmt3a could provide feedback to the PI3K/Akt signaling pathway and play a role in maintaining cell survival ( Wang et al., 2020 ). Furthermore, CE-mediated recovery of CaM was impaired by 5-AZ, an inhibitor of Dnmts.…”
We previously demonstrated the antioxidant activity of Coeloglossum viride var. bracteatum extract (CE) in rat cortical neurons and in mice with chemically induced cognitive impairment. In this work, we established a staurosporine (STS)-induced toxicity model to decipher the neuroprotective mechanisms of CE. We found that CE protected cell viability and neurite integrity in STS-induced toxicity by restoring the levels of FGF2 and its associated PI3K/Akt signaling axis. LY294002, a pan-inhibitor of PI3K, antagonized the activity of CE, although its-mediated restoration of FGF2 was unaffected. In addition, CE restored levels of Bcl-2/Caspase-3, PKCα/CaM pathway, and Dnmt3a and Dnmt3b, two methyltransferases that contribute to de novo DNA methylation. The Dnmts inhibitor 5-azacytidine impaired CE-mediated restoration of Dnmt3 or CaM, as well as the transition of DNA methylation status on the Dnmt3 promoter. These results reveal potential mechanisms that could facilitate the study and application of CE as a neuroprotective agent.
“…The study demonstrated that continuous administration of Dnmt3a to the tibialis anterior muscle significantly counteracted streptozotocin (STZ)-induced DM muscle atrophy and enhanced myotube formation in C2C12 myoblasts. Crucially, Dnmt3a overexpression also reinstated the expression levels of atrophy genes such as MAFbx , MuRF1 , MyoD , and Myog , both in vivo and in vitro [ 55 ]. Fig.…”
Section: The Role Of Epigenetic In Skeletal Muscle Atrophymentioning
Skeletal muscular atrophy is a complex disease involving a large number of gene expression regulatory networks and various biological processes. Despite extensive research on this topic, its underlying mechanisms remain elusive, and effective therapeutic approaches are yet to be established. Recent studies have shown that epigenetics play an important role in regulating skeletal muscle atrophy, influencing the expression of numerous genes associated with this condition through the addition or removal of certain chemical modifications at the molecular level. This review article comprehensively summarizes the different types of modifications to DNA, histones, RNA, and their known regulators. We also discuss how epigenetic modifications change during the process of skeletal muscle atrophy, the molecular mechanisms by which epigenetic regulatory proteins control skeletal muscle atrophy, and assess their translational potential. The role of epigenetics on muscle stem cells is also highlighted. In addition, we propose that alternative splicing interacts with epigenetic mechanisms to regulate skeletal muscle mass, offering a novel perspective that enhances our understanding of epigenetic inheritance’s role and the regulatory network governing skeletal muscle atrophy. Collectively, advancements in the understanding of epigenetic mechanisms provide invaluable insights into the study of skeletal muscle atrophy. Moreover, this knowledge paves the way for identifying new avenues for the development of more effective therapeutic strategies and pharmaceutical interventions.
“…Thus, the AKT/ PTEN pathway is critical for skeletal muscle hypertrophy and prevention of muscle atrophy. 17 Our previous studies have shown that lifelong exercise-activated PTEN/AKT pathway and indirectly inhibited the HIPPO pathway activation. 18 Therefore, we investigated whether HIIT acts on HIPPO pathway to prevent muscle atrophy along with regulating AKT/PTEN pathway.…”
Section: Introductionmentioning
confidence: 97%
“…In addition, intracellular PTEN pathway activation inhibited AKT pathway activity and induced apoptosis. Thus, the AKT/PTEN pathway is critical for skeletal muscle hypertrophy and prevention of muscle atrophy 17 . Our previous studies have shown that lifelong exercise‐activated PTEN/AKT pathway and indirectly inhibited the HIPPO pathway activation 18 .…”
Exercise‐induced microRNA (miRNA) and HIPPO pathways participate in the regulation of skeletal muscle plasticity but their underlying mechanisms remain unclear. We aimed to investigate the effect of high‐intensity interval training (HIIT) on miRNA expression and the HIPPO pathway in the skeletal muscle of aging rats to determine its role in the amelioration of muscle aging. Thirty‐six 18‐month‐old female rats were randomly divided into sedentary control (SED, n = 12), moderate‐intensity continuous training (MICT, n = 12), and HIIT (n = 12) groups, with continuous exercise for 8 months. Quantitative reverse transcription‐polymerase chain reaction, immunoblotting, KEGG enrichment, and dual‐luciferase assays were performed on the target skeletal muscle. Compared with the SED group, the MICT and HIIT groups showed a significant trend of improvement in Lee's index and grip strength and a marked increase in skeletal muscle mitochondrial function, apoptosis, antioxidant, and lipolysis‐related protein expression. They also exhibited PI3K/AKT pathway activation and a decrease in expression of HIPPO pathway‐related proteins; 20 miRNAs were differentially expressed and enriched in the exercise group compared with the SED group, including the HIPPO pathway and metabolic pathways. Further analysis of L6 cells confirmed that miR‐182 may target PTEN, which indirectly regulates HIPPO signaling, but not Mob1. the combined application of HIIT and MICT increased the antioxidant and lipolytic capacities of skeletal muscle and improved atrophy of aging skeletal muscle; HIIT was more effective than MICT. This may be related to HIIT‐mediated AKT pathway activation and HIPPO pathway inhibition by miRNAs (miR‐486 and miR‐182).
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