The anticancer agent doxorubicin disrupts mitochondrial energy metabolism and redox balance in skeletal muscle.
The anticancer agent doxorubicin disrupts mitochondrial energy metabolism and redox balance in skeletal muscle.
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DOI：
10.1016/j.freeradbiomed.2013.08.191
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发表时间：
2013-12
影响因子：
7.4
通讯作者：
Neufer, P. Darrell
中科院分区：
文献类型：
--
作者：
Gilliam, Laura A. A.;Fisher-Wellman, Kelsey H.;Lin, Chien-Te;Maples, Jill M.;Cathey, Brook L.;Neufer, P. Darrell
对于接受化疗的癌症患者来说，肌肉力量的丧失和持续的疲劳是使他们失去能力的症状。阿霉素是临床上使用的一种标准化疗药物，它会导致骨骼肌功能障碍和过早疲劳，并伴随着活性氧自由基(ROS)的增加。由于线粒体是肌肉中氧化剂产生的主要来源，我们假设阿霉素可以通过抑制呼吸能力对线粒体产生负面影响，导致过氧化氢释放潜力增加。在这里，我们展示了骨骼肌线粒体对单次注射阿霉素(20 mg/kg)的双相反应。在最初的2 h，阿霉素抑制I和II复合体支持的呼吸并增加H_2O_2的释放，24 h后两者均部分恢复。24 h时氧耗与膜电位(Δψ)的关系右移，表明电子传递系统(Ets)内还原压力升高。呼吸能力在随后的时间点(72h)进一步降低，并伴随着H_2O_2释放电位和对线粒体通透性转换孔(MPTP)开放的敏感性增加。这些新的发现表明，骨骼肌线粒体是阿霉素诱导的肌肉功能障碍的潜在潜在原因。
The combined loss of muscle strength and constant fatigue are disabling symptoms for cancer patients undergoing chemotherapy. Doxorubicin, a standard chemotherapy drug used in the clinic, causes skeletal muscle dysfunction and premature fatigue along with an increase in reactive oxygen species (ROS). As mitochondria represent a primary source of oxidant generation in muscle, we hypothesized doxorubicin could negatively effect mitochondria by inhibiting respiratory capacity, leading to an increase in H2O2 emitting potential. Here we demonstrate a biphasic response of skeletal muscle mitochondria to a single doxorubicin injection (20 mg/kg). Initially at 2 h doxorubicin inhibits both complex I- and II-supported respiration and increases H2O2 emission, both of which are partially restored after 24 h. The relationship between oxygen consumption and membrane potential (Δψ) is shifted to the right at 24 h, indicating elevated reducing pressure within the electron transport system (ETS). Respiratory capacity is further decreased at a later timepoint (72 h) along with H2O2 emitting potential and an increased sensitivity to mitochondrial permeability transition pore (mPTP) opening. These novel findings suggest a role for skeletal muscle mitochondria as a potential underlying cause of doxorubicin-induced muscle dysfunction.
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DOI：
10.1152/ajplung.00264.2010
发表时间：
2011-02-01
影响因子：
4.9
作者：
Gilliam, Laura A. A.;Moylan, Jennifer S.;Reid, Michael B.
通讯作者：
Reid, Michael B.
影响因子：
15.9
作者：
Anderson, Ethan J.;Lustig, Mary E.;Neufer, P. Darrell
通讯作者：
Neufer, P. Darrell
影响因子：
3.3
作者：
Gilliam, Laura A. A.;Ferreira, Leonardo F.;Reid, Michael B.
通讯作者：
Reid, Michael B.
影响因子：
5.5
作者：
Gilliam, Laura A. A.;Moylan, Jennifer S.;Reid, Michael B.
通讯作者：
Reid, Michael B.
DOI：
10.1152/ajpcell.1996.270.2.c673
发表时间：
1996-02-01
影响因子：
5.5
作者：
Jackman, MR;Willis, WT
通讯作者：
Willis, WT