Meng Xiangyuan, Tian Chunyan, Xie Chenqi, Zhang Hao, Wang Haoyu, Zhang Mai, Lu Zhenquan, Li Duo, Chen Lei, Gao Tianlin
School of Public Health, Qingdao University, Qingdao 266071, China.
Institute of Nutrition & Health, Qingdao University, Qingdao 266021, China.
Food Funct. 2023 Apr 3;14(7):3126-3138. doi: 10.1039/d2fo03926e.
The function of skeletal muscles can be markedly hampered by obesity. Ten-eleven translocation 2 (TET2) is an important therapeutic target for ameliorating skeletal muscle dysfunction. Our previous study revealed that punicalagin (PUN) regulated TET2 in obese mice; however, whether PUN can prevent obesity-induced skeletal muscle dysfunction by regulating TET2 remains unclear. In the present study, 40 male C57BL/6J mice were divided into four groups ( = 10 per group): the control (CON) group, the high-fat-diet (HFD, negative control) group, the resveratrol (positive control) group, and the PUN group. The ratio of gastrocnemius weight to body weight (0.0097 ± 0.0016 0.0080 ± 0.0011), the grip strength (120.04 g ± 11.10 98.89 g ± 2.79), and the muscle fiber count (314.56 per visual field ± 92.73 236.44 per visual field ± 50.58) in the PUN group were higher than those in the HFD group. Moreover, the levels of the TET2 protein, 5-hydroxymethylcytosine (5hmC), and 5-formylcytosine (5fC) in skeletal muscles were significantly lower in the HFD group than those in the CON group; these levels increased after PUN treatment. Compared with the HFD group, the phosphorylation level of AMP-activated protein kinase (AMPK) α in the PUN group was higher, which effectively enhanced the stability of the TET2 protein. Besides, the ratio of (succinic acid + fumaric acid)/α-ketoglutarate in the PUN group was lower than that in the HFD group (43.21 ± 12.42 99.19 ± 37.07), and a lower ratio led to a higher demethylase activity of TET2 in the PUN group than in the HFD group. This study highlights that PUN supplementation protects against obesity-induced impairment of the skeletal muscle function regulating the protein stability of TET2 and the enzymatic activity of TET2 demethylation.
肥胖会显著妨碍骨骼肌的功能。10-11易位蛋白2（TET2）是改善骨骼肌功能障碍的一个重要治疗靶点。我们之前的研究表明，石榴皮素（PUN）在肥胖小鼠中调节TET2；然而，PUN是否能通过调节TET2预防肥胖诱导的骨骼肌功能障碍仍不清楚。在本研究中，40只雄性C57BL/6J小鼠被分为四组（每组n = 10）：对照组（CON）、高脂饮食（HFD，阴性对照）组、白藜芦醇（阳性对照）组和PUN组。PUN组腓肠肌重量与体重之比（0.0097±0.0016对0.0080±0.0011）、握力（120.04 g±11.10对98.89 g±2.79）和肌纤维计数（每视野314.56±92.73对每视野236.44±50.58）均高于HFD组。此外，HFD组骨骼肌中TET2蛋白、5-羟甲基胞嘧啶（5hmC）和5-甲酰基胞嘧啶（5fC）水平显著低于CON组；PUN处理后这些水平升高。与HFD组相比，PUN组AMP激活的蛋白激酶（AMPK）α的磷酸化水平更高，这有效地增强了TET2蛋白的稳定性。此外，PUN组（琥珀酸+富马酸）/α-酮戊二酸的比值低于HFD组（43.21±12.42对99.19±37.07），较低的比值导致PUN组TET2的去甲基酶活性高于HFD组。本研究强调，补充PUN可通过调节TET2的蛋白稳定性和TET2去甲基化的酶活性来预防肥胖诱导的骨骼肌功能损害。
