Effects of short-term endurance exercise training on acute doxorubicin-induced FoxO transcription in cardiac and skeletal muscle
Effects of short-term endurance exercise training on acute doxorubicin-induced FoxO transcription in cardiac and skeletal muscle
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DOI：
10.1152/japplphysiol.00210.2014
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发表时间：
2014-08-01
影响因子：
3.3
通讯作者：
Powers, Scott K.
中科院分区：
文献类型：
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作者：
Kavazis, Andreas N.;Smuder, Ashley J.;Powers, Scott K.
阿霉素（DOX）是一种有效的抗肿瘤药物，用于癌症治疗。不幸的是，DOX可诱导心肌和骨骼肌肌病，这限制了其临床应用。重要的是，运动训练已被证明可以预防dox介导的心脏和骨骼肌肌病。然而，这种运动诱导的肌肉保护机制仍然难以捉摸。这些实验验证了一种假设，即短期运动训练可以防止dox引起的急性肌肉毒性，部分原因是萎缩基因的叉形盒O （FoxO）转录减少。大鼠（每组n = 6）被分配到久坐或耐力运动训练组，并与安慰剂或DOX治疗配对。在心脏和骨骼肌中测量基因表达和蛋白丰度，以确定DOX和运动对FoxO基因靶点的影响。我们的数据表明，DOX增加了FoxO1和FoxO3 mRNA的表达，并增加了FoxO靶基因[即萎缩素-1/肌肉萎缩F-box (MaFbx)，肌肉环指-1 （MuRF-1）和BCL2/腺病毒E1B 19kda蛋白相互作用蛋白3 (BNIP3)]在心脏和比目鱼肌中的转录。重要的是，运动训练可以防止dox诱导心肌中FoxO1和MuRF-1的增加，也可以防止比目鱼肌中FoxO3、MuRF-1和BNIP3的增加。此外，我们的研究结果表明，运动增加了心脏和比目鱼肌中过氧化物酶体增殖激活受体- γ辅助激活因子-1 α (PGC-1 α)。这一点很重要，因为已知PGC-1 α表达增加会抑制FoxO活性，导致FoxO靶基因表达减少。总之，这些结果与运动训练保护心脏（FoxO1和MuRF-1）和骨骼肌（FoxO3， MuRF-1和BNIP3）免受dox诱导的肌病的假设是一致的。
Doxorubicin (DOX) is a potent antitumor agent used in cancer treatment. Unfortunately, DOX can induce myopathy in both cardiac and skeletal muscle, which limits its clinical use. Importantly, exercise training has been shown to protect against DOX-mediated cardiac and skeletal muscle myopathy. However, the mechanisms responsible for this exercise-induced muscle protection remain elusive. These experiments tested the hypothesis that short-term exercise training protects against acute DOX-induced muscle toxicity, in part, due to decreased forkhead-box O (FoxO) transcription of atrophy genes. Rats (n = 6 per group) were assigned to sedentary or endurance exercise-trained groups and paired with either placebo or DOX treatment. Gene expression and protein abundance were measured in both cardiac and skeletal muscles to determine the impact of DOX and exercise on FoxO gene targets. Our data demonstrate that DOX administration amplified FoxO1 and FoxO3 mRNA expression and increased transcription of FoxO target genes [i.e., atrogin-1/muscle atrophy F-box (MaFbx), muscle ring finger-1 (MuRF-1), and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)] in heart and soleus muscles. Importantly, exercise training protected against DOX-induced increases of FoxO1 and MuRF-1 in cardiac muscle and also prevented the rise of FoxO3, MuRF-1, and BNIP3 in soleus muscle. Furthermore, our results indicate that exercise increased peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) in both the heart and soleus muscles. This is important because increased PGC-1 alpha expression is known to suppress FoxO activity resulting in reduced expression of FoxO target genes. Together, these results are consistent with the hypothesis that exercise training protects against DOX-induced myopathy in both heart (FoxO1 and MuRF-1) and skeletal muscles (FoxO3, MuRF-1, and BNIP3).