Mitochondrial-targeted Antioxidants, Aging and AZT in Skeletal Muscle Dysfunction

这项修订后的提案建立在我们令人兴奋的初步发现的基础上，证明了 线粒体靶向抗氧化剂保护骨骼肌免受齐多夫定(AZT)诱导的功能障碍。 由于艾滋病毒治疗的成功，其中通常包括AZT，美国超过35%的艾滋病毒携带者是 50岁及以上。新数据表明，AZT引起的变化在年轻人和老年人中是非常不同的 骨骼肌。然而，这些救命疗法与线粒体衰老之间的相互作用 保持贫乏的理解。AZT和其他核苷逆转录酶抑制剂(NRT1)具有显著的 线粒体毒性与衰老的肌肉有许多相同的特征，包括线粒体增加 突变，线粒体含量减少，能量产生受损，氧化应激增加 导致肌肉萎缩和虚弱。尽管有这些相似之处，但还没有研究检验 衰老和NRT1治疗对骨骼肌线粒体功能的潜在协同效应。在这 建议，我们使用一种常见的NRT1组合，AZT/3TC(Combivir)来测试衰老是否加剧 NRTI诱导的线粒体毒性以及线粒体靶向抗氧化剂能否阻止这种毒性 线粒体功能障碍。目标1(Funcfion)使用最先进的光谱和传统方法来 检测衰老是否加重AZT/3TC处理的肌肉的功能衰退，以及线粒体是否 靶向过氧化氢酶(MCAT)能够阻止这种下降。目标2(机制)阐明了细胞 AZT/3TC对幼龄和老年小鼠肌肉AZT/3TC毒性和MCAT保护作用的机制我们 在上一个P01赠款周期中开发的综合方法来测量线粒体的变化 蛋白质组、损伤和质量控制过程。目标3(翻译)测试翻译的潜力 转基因MCAT模型对人体应用的保护作用我们测试新开发的 线粒体靶向抗氧化肽(SS肽)对AZT/3TC毒性的保护作用 和老老鼠的肌肉。我们结合了目标1和目标2的方法来测量体内的功能结果 以及保护SS ofides的内在机制。‘ 相关性(请参阅说明)： 这项研究对于开发新的干预措施以减少糖尿病的病理变化具有很大的潜力。 ROS产生和线粒体功能障碍导致虚弱的条件，如衰老、艾滋病毒、癌症 和神经退化。与项目1、2和3的密切合作提供了一个独特的机会 确定如何优化线粒体靶向抗氧化剂以达到治疗多发性疾病的最佳效果 和器官系统

This revised proposal builds on our exciting preliminary findings demonstrafing the power of a mitochondrially targeted anfioxidant to protect skeletal muscle from zidovudine (AZT)-induced dysfuncfion. Due to the success of HIV treatments, which often includes AZT, over 35% of all HIV pafients in the US are 50 years and older. New data demonstrates that AZT-induced changes are very different in young and old skeletal muscle. However, the interacfions between these life-saving therapies and aging on mitochondria remain pooriy understood. AZT and other nucleoside reverse transcriptase inhibitors (NRTl) have significant mitochondrial toxicity that shares many characteristics with aging muscle, including increased mitochondrial mutafions, reduced mitochondrial content, impaired energy producfion, and increased oxidative stress leading to muscle loss and frailty. Despite these similarifies, there have been no studies examining the potential synergisfic effects of aging and NRTl treatment on mitochondrial function in skeletal muscle. In this proposal, we use a common NRTl combinafion, AZT/3TC (combivir), to test whether aging exacerbates NRTI-induced mitochondrial toxicity and whether mitochondrially targeted antioxidants can prevent this mitochondrial dysfuncfion. Aim 1 (Funcfion) uses state of the art spectroscopic and tradifional approaches to test whether aging worsens the functional decline in AZT/3TC treated muscle and whether mitochondrially targeted catalase (mCAT) is able to prevent this decline. Aim 2 (Mechanism) elucidates the cellular mechanisms underlying AZT/3TC toxicity and mCAT protecfion in young and old mouse muscle. We combine methods developed during the last P01 grant cycle for measuring changes in the mitochondrial proteome, damage, and quality control processes. Aim 3 (Translation) tests the potential for translating the protective effects of the transgenic mCAT model to human application. We test whether newly developed mitochondrially targeted anfioxidant pepfides (SS pepfides) can protect against AZT/3TC toxicity in young and old mouse muscles. We combine methods from Aims 1 and 2 to measure in vivo functional outcomes and underivino mechanisms of orotection of the SS oeofides. ' RELEVANCE (See instructions): This study has great translafional potenfial for developing new intervenfions to reduce pathology in condifions where ROS producfion and mitochondrial dysfunction lead to frailty, such as aging, HIV, cancer and neurodegeneration. The close collaboration with Projects 1, 2 and 3 presents a unique opportunity to determine how mitochondrially targeted antioxidants can be opfimized for best effects in mulfiple disease and organ systems