Involvement of oxidative stress and caspase 2-mediated intrinsic pathway signaling in age-related increase in muscle cell apoptosis in mice
Involvement of oxidative stress and caspase 2-mediated intrinsic pathway signaling in age-related increase in muscle cell apoptosis in mice
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DOI：
10.1007/s10495-008-0216-7
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发表时间：
2008-06-01
期刊：
影响因子：
7.2
通讯作者：
Sinha-Hikim, Indrani
中科院分区：
文献类型：
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作者：
Braga, Melissa;Hikim, Amiya P. Sinha;Sinha-Hikim, Indrani
细胞凋亡被认为是正常衰老过程中肌细胞损失的一种机制，在年龄相关性肌减少症中起着重要作用。为了验证caspase 2和c-Jun氨基末端激酶（JNK）介导的内在途径信号传导有助于衰老中骨骼肌细胞凋亡的假设，我们比较了caspase 2和JNK的活化以及4-羟基壬烯醛蛋白加合物（4-HNE）、诱导型一氧化氮合酶（iNOS）、葡萄糖-6-磷酸脱氢酶（G6 PDH）、B细胞淋巴瘤-2（BCL-2）、BAX、以及年轻（5月龄）和老年（25月龄）小鼠腓肠肌中的磷酸化BCL-2。在小鼠中很容易检测到4-HNE和iNOS表达的明显年龄相关性增加。增加氧化应激和诱导型一氧化氮合酶的诱导进一步伴随着G6 PDH表达的减少，半胱天冬酶2和JNK的激活，以及通过丝氨酸70磷酸化和半胱天冬酶9激活的BCL-2的失活。回归分析进一步揭示，衰老中增加的肌细胞死亡与这些分子水平的变化显著相关。综上所述，我们的数据表明，caspase 2和JNK介导的内在途径信号转导是参与肌细胞凋亡的年龄相关性增加的机制之一。
Apoptosis has been implicated as a mechanism of loss of muscle cells in normal aging and plays an important role in age-related sarcopenia. To test the hypothesis that caspase 2 and c-Jun NH2-terminal kinase (JNK)-mediated intrinsic pathway signaling contribute to skeletal muscle cell apoptosis in aging, we compared activation of caspase 2 and JNK and the in vivo expression of 4-hydroxynonenal protein adducts (4-HNE), inducible nitric oxide synthase (iNOS), glucose-6-phosphate dehydrogenase (G6PDH), B-cell lymphoma-2 (BCL-2), BAX, and phospho-BCL-2 in gastrocnemius muscles of young (5 months old) and old (25 months old) mice. A distinct age-related increase in 4-HNE and iNOS expression was readily detected in mice. Increased oxidative stress and iNOS induction were further accompanied by a decrease in G6PDH expression, activation of caspase 2 and JNK, and inactivation of BCL-2 through phosphorylation at serine 70, and caspase 9 activation. Regression analysis further revealed that increased muscle cell death in aging was significantly correlated with changes in the levels of these molecules. Taken together, our data indicate that caspase 2 and JNK-mediated intrinsic pathway signaling is one of the mechanisms involved in age-related increase in muscle cell apoptosis.