Department of Physiology, College of Medicine, Yeungnam University, Daegu, Republic of Korea; Smart-aging Convergence Research Center, College of Medicine, Yeungnam University, Daegu, Republic of Korea.
Smart-aging Convergence Research Center, College of Medicine, Yeungnam University, Daegu, Republic of Korea; Department of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, Daegu, Republic of Korea.
Exp Gerontol. 2019 Oct 15;126:110711. doi: 10.1016/j.exger.2019.110711. Epub 2019 Aug 24.
Skeletal muscle atrophy reduces quality of life and increases morbidity and mortality in patients with chronic conditions. Oxidative stress is a key factor contributing to skeletal muscle atrophy by altering both protein synthesis and protein degradation pathways. Beta-lapachone (Beta-L) is known to act as a pro-oxidant in cancer cells but suppresses oxidative stress in normal cells and tissues. In the present study, we examined whether Beta-L (100 mg/kg body weight) prevents immobilization-induced skeletal muscle atrophy in male C57BL/6N mice. Skeletal muscle atrophy was induced by immobilization of left hindlimbs for two weeks, and right hindlimbs were used as controls. The muscle weights of gastrocnemius (0.132 ± 0.003 g vs. 0.115 ± 0.003 g in Beta-L and SLS, respectively, p < 0.01) and tibialis anterior (0.043 ± 0.001 vs. 0.027 ± 0.002 in Beta-L and SLS, respectively, p < 0.001) were significantly heavier in Beta-L-treated mice than that in SLS-treated mice in immobilization group, which was accompanied by improved skeletal muscle function as tested by treadmill exhaustion and grip strength test. Immobilization increased HO levels, while Beta-L treatment normalized such levels (1.6 ± 0.16 μM vs. 2.7 ± 0.44 μM in Beta-L and vehicle, respectively, p < 0.05). Oxidative stress makers were also normalized by Beta-L treatment. Protein synthesis signaling pathways were unaltered in the case of both immobilization and Beta-L treatment. However, protein catabolic, ubiquitin-proteasomal, and autophagy-lysosomal pathways were stimulated by immobilization and were normalized by Beta-L treatment. Upregulation of transforming growth factor β and Smad 2/3 after immobilization was significantly diminished by Beta-L treatment. These results suggest that Beta-L attenuates the loss of muscle weight and function induced by immobilization through suppression of oxidative stress.
骨骼肌萎缩降低了慢性病患者的生活质量，并增加了发病率和死亡率。氧化应激是导致骨骼肌萎缩的一个关键因素，它改变了蛋白质合成和蛋白质降解途径。β-拉帕醌（Beta-L）已知在癌细胞中作为一种促氧化剂，但在正常细胞和组织中抑制氧化应激。在本研究中，我们研究了 Beta-L（100mg/kg 体重）是否可以预防雄性 C57BL/6N 小鼠因固定引起的骨骼肌萎缩。通过固定左后肢两周来诱导骨骼肌萎缩，而右后肢作为对照。与 SLS 处理组相比，Beta-L 处理组的腓肠肌（0.132±0.003g 比 0.115±0.003g，p<0.01）和比目鱼肌（0.043±0.001 比 0.027±0.002，p<0.001）的肌肉重量明显更重，这伴随着跑步机衰竭和握力测试等骨骼肌功能的改善。固定增加了 HO 水平，而 Beta-L 处理使这些水平正常化（Beta-L 组为 1.6±0.16μM，而载体组为 2.7±0.44μM，p<0.05）。氧化应激标志物也被 Beta-L 处理正常化。固定和 Beta-L 处理都没有改变蛋白质合成信号通路。然而，蛋白质分解、泛素-蛋白酶体和自噬溶酶体途径在固定后被刺激，并被 Beta-L 处理正常化。固定后转化生长因子β和 Smad2/3 的上调被 Beta-L 处理显著减弱。这些结果表明，Beta-L 通过抑制氧化应激来减轻固定引起的肌肉重量和功能丧失。
