Medical Research Center of Shengjing Hospital, China Medical University, Shenyang 110004, China; Key Laboratory of Research and Application of Animal Model for Environmental and Metabolic Diseases, Liaoning Province, China.
Medical Research Center of Shengjing Hospital, China Medical University, Shenyang 110004, China; Key Laboratory of Research and Application of Animal Model for Environmental and Metabolic Diseases, Liaoning Province, China.
Life Sci. 2019 Oct 15;235:116800. doi: 10.1016/j.lfs.2019.116800. Epub 2019 Aug 28.
It is well known that cigarette smoke (CS) is the main risk factor for chronic obstructive pulmonary disease (COPD) accompanied by skeletal muscle atrophy. Histone deacetylases (HDACs) that remove acetyl groups from target proteins are necessary for the muscle atrophy associated with skeletal muscle disuse. However, the role of HDACs and trichostatin A (TSA), a HDAC inhibitor, in skeletal muscle atrophy caused by CS exposure remains poorly understood.
Female mice were exposed to CS twice daily for 40 days and TSA injected intraperitoneally into CS-exposed mice on alternate days. Skeletal muscles were weighed and gastrocnemius (Gas) muscle histomorphology examined by hematoxylin and eosin staining. Histone deacetylases 1 and 2 (HDAC1/2), and markers of ubiquitin degradation, muscle differentiation, apoptosis, pyroptosis, and the cytoskeletal proteins were assessed by western blot and immunohistochemistry in Gas.
CS exposure decreased body and skeletal muscle weights and triggered an increase in the percentage of fiber with centralized nuclei in Gas. HDAC1/2 proteins were upregulated in the Gas of mice exposed to CS, while TSA effectively inhibited HDAC1/2 protein levels and attenuated the loss of body weight and skeletal muscle wet weight induced by CS exposure. Markers for ubiquitin degradation, muscle differentiation, cytoskeletal proteins, apoptosis and pyroptosis were all upregulated following CS exposure and effectively restored by TSA.
TSA may inhibit skeletal muscle atrophy and histomorphological alterations induced by CS exposure by downregulating markers of ubiquitin degradation, muscle fiber differentiation, cytoskeletal proteins, apoptosis and pyroptosis via HDAC1/2 inhibition.
众所周知，香烟烟雾（CS）是慢性阻塞性肺疾病（COPD）的主要危险因素，同时伴有骨骼肌萎缩。从靶蛋白上去除乙酰基的组蛋白去乙酰化酶（HDACs）对于与骨骼肌废用相关的肌肉萎缩是必要的。然而，HDACs 的作用以及组蛋白去乙酰化酶抑制剂（TSA）在 CS 暴露引起的骨骼肌萎缩中的作用仍知之甚少。
雌性小鼠每天两次暴露于 CS 中 40 天，并在 CS 暴露的小鼠中隔日腹膜内注射 TSA。称重骨骼肌，通过苏木精和伊红染色检查比目鱼肌（Gas）肌肉组织形态。通过 Western blot 和免疫组化评估 Gas 中组蛋白去乙酰化酶 1 和 2（HDAC1/2）以及泛素降解、肌肉分化、凋亡、焦亡和细胞骨架蛋白的标志物。
CS 暴露降低了体重和骨骼肌重量，并导致 Gas 中纤维的中央核比例增加。CS 暴露的小鼠中 HDAC1/2 蛋白上调，而 TSA 有效抑制了 HDAC1/2 蛋白水平，并减轻了 CS 暴露引起的体重和骨骼肌湿重的丧失。CS 暴露后泛素降解、肌肉分化、细胞骨架蛋白、凋亡和焦亡的标志物均上调，而 TSA 有效恢复了这些标志物。
TSA 可能通过抑制 HDAC1/2 来抑制 CS 暴露引起的骨骼肌萎缩和组织形态学改变，从而下调泛素降解、肌肉纤维分化、细胞骨架蛋白、凋亡和焦亡的标志物。
