Wang Manfeng, Wu Xiaowei, Gan Lu, Teng Zongyan, Zhang Haijin, Zhang Yina
First Department of Cadre's Ward, The Second Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China.
Third Department of Cadre's Ward, The Second Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China.
Exp Physiol. 2020 Nov;105(11):1918-1927. doi: 10.1113/EP088894. Epub 2020 Sep 24.
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 prevent muscle atrophy in patients with diabetes.
Muscle atrophy is one of the major long-term complications of diabetes mellitus, which greatly affects the mobility of patients. Epigenetic processes mediated by DNA methyltransferases (DNMTs) play crucial roles in the locomotor system, but little is known about the functions of DNMTs in diabetic muscle atrophy. Here, we investigated the function of Dnmt3a in diabetic muscle atrophy and explored the mechanisms involved. Adeno-associated virus AAV2 overexpressing Dnmt3a or its vector control was injected into the tibialis anterior muscle of streptozotocin-induced diabetic mice. Muscle mass and muscle cross-sectional area were used to evaluate muscle atrophy. In vitro, adeno-associated virus AAV2 overexpressing Dnmt3a or its vector control was transfected into C2C12 myoblasts. Horse serum was used to induce differentiation and palmitate to stimulate the C2C12 myoblasts. The expressions of myogenic regulatory factors were examined by real-time PCR and western blot analysis. Overexpression of Dnmt3a attenuated muscle atrophy in diabetic mice and promoted myotube formation of C2C12 myoblasts. Overexpression of Dnmt3a restored the expressions of myogenic regulatory factors atrogin-1, MuRF1, Pax7, Myod1 and myogenin, both in vivo and in vitro. Moreover, overexpression of Dnmt3a activated the phosphorylation of Akt by inhibiting the activation of Pten. This study demonstrates that overexpression of Dnmt3a prevents diabetic muscle atrophy by modulating the Pten/Akt pathway.
本研究的核心问题是什么？Dnmt3a在调节糖尿病性肌肉萎缩中是否起关键作用？主要发现及其重要性是什么？肌肉萎缩是糖尿病的主要长期并发症之一。然而，对其涉及的分子机制知之甚少。在本文中，我们证明Dnmt3a过表达可有效改善小鼠的糖尿病性肌肉健康，并记录了其潜在机制。DNMT3A可能成为预防糖尿病患者肌肉萎缩的一个有前景的靶点。
肌肉萎缩是糖尿病的主要长期并发症之一，严重影响患者的活动能力。由DNA甲基转移酶（DNMTs）介导的表观遗传过程在运动系统中起关键作用，但关于DNMTs在糖尿病性肌肉萎缩中的功能知之甚少。在此，我们研究了Dnmt3a在糖尿病性肌肉萎缩中的功能，并探讨了其涉及的机制。将过表达Dnmt3a的腺相关病毒AAV2或其载体对照注射到链脲佐菌素诱导的糖尿病小鼠的胫前肌中。用肌肉质量和肌肉横截面积评估肌肉萎缩。在体外，将过表达Dnmt3a的腺相关病毒AAV2或其载体对照转染到C2C12成肌细胞中。用马血清诱导分化，用棕榈酸刺激C2C12成肌细胞。通过实时PCR和蛋白质印迹分析检测成肌调节因子的表达。Dnmt3a过表达减轻了糖尿病小鼠的肌肉萎缩，并促进了C2C12成肌细胞的肌管形成。Dnmt3a过表达在体内和体外均恢复了成肌调节因子atrogin-1、MuRF1、Pax7、Myod1和肌细胞生成素的表达。此外，Dnmt3a过表达通过抑制Pten的激活来激活Akt的磷酸化。本研究表明，Dnmt3a过表达通过调节Pten/Akt途径预防糖尿病性肌肉萎缩。
