During aging, organs such as skeletal muscle and heart require sufficient NAD⁺ both as a coenzyme for oxidative-reductive electron transfer and as a substrate for multiple signaling pathways. Sirtuins (SIRTs), a family of NAD⁺-dependent deacetylase, play an important role in regulating mitochondrial homeostasis and antioxidant defense by deacetylating transcription factors and enzymes such as PGC-1α, p65, GCN5, and SOD2. However, age-related DNA damage and increased SASP activate PARP-1 and CD38, the enzymes competing with SIRTs for NAD⁺. Thus, it is important to know how aging alters intracellular NAD⁺ status and NAD⁺-depending enzyme expression in muscles. In this study, we report that the acetylation level of muscle protein pool, as well as major SIRTs target proteins (PGC-1α, GCN5, p65, and SOD2), was significantly increased in hindlimb and cardiac muscles of 24-month old mice compared with their 6-month old counterparts, despite the fact that most members of the SIRT family were upregulated with aging. Aging increased the protein content of PARP-1 and CD38, whereas decreased NAD⁺ levels in both skeletal and heart muscles. Aged muscles demonstrated clear signs of mitochondrial dysfunction, oxidative stress, and inflammation. Taken together, our data suggest that despite the upregulation of SIRTs, aged muscles suffered from NAD⁺ deficit partly due to the competition of elevated CD38 and PARP-1. The enhanced acetylation of several key proteins involved in broad cellular functions may contribute to the age-related muscle deterioration.

中文翻译：

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衰老会改变骨骼肌和心肌的乙酰化状态。

在衰老过程中，骨骼肌和心脏等器官需要足够的 NAD ⁺，既作为氧化还原电子转移的辅酶，又作为多种信号通路的底物。^{Sirtuins (SIRTs) 是 NAD +}依赖性脱乙酰酶家族，通过脱乙酰转录因子和酶（如 PGC-1α、p65、GCN5 和 SOD2），在调节线粒体稳态和抗氧化防御中发挥重要作用。然而，与年龄相关的 DNA 损伤和增加的 SASP 会激活 PARP-1 和 CD38，这些酶与 SIRT 竞争 NAD ⁺。因此，了解衰老如何改变肌肉中细胞内 NAD ⁺状态和 NAD ⁺依赖酶的表达非常重要。在这项研究中，我们报告说，与 24 个月大的小鼠相比，24 个月大的小鼠后肢和心肌中肌肉蛋白库以及主要 SIRT 靶蛋白（PGC-1α、GCN5、p65 和 SOD2）的乙酰化水平显着增加。尽管事实上 SIRT 家族的大多数成员随着年龄的增长而上调。衰老会增加骨骼肌和心肌中PARP-1 和 CD38 的蛋​​白质含量，而降低 NAD ^+水平。衰老的肌肉表现出明显的线粒体功能障碍、氧化应激和炎症迹象。总而言之，我们的数据表明，尽管 SIRT 上调，但衰老的肌肉仍遭受 NAD ⁺缺陷，部分原因是 CD38 和 PARP-1 升高的竞争。参与广泛细胞功能的几种关键蛋白质的乙酰化增强可能导致与年龄相关的肌肉退化。