The loss of cardiac SIRT3 decreases metabolic flexibility and proteostasis in an age-dependent manner.
The loss of cardiac SIRT3 decreases metabolic flexibility and proteostasis in an age-dependent manner.
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DOI：
10.1007/s11357-022-00695-0
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发表时间：
2023-04
期刊：
影响因子：
5.6
通讯作者：
Humphries, Kenneth M.
中科院分区：
文献类型：
--
作者：
Li, Ping;Newhardt, Maria F.;Matsuzaki, Satoshi;Eyster, Craig;Pranay, Atul;Peelor, Frederick F. I. I. I. I. I. I.;Batushansky, Albert;Kinter, Caroline;Subramani, Kumar;Subrahmanian, Sandeep;Ahamed, Jasimuddin;Yu, Pengchun;Kinter, Michael;Miller, Benjamin F.;Humphries, Kenneth M.
SIRT 3是一种长寿因子，在线粒体中充当主要的脱乙酰酶。尽管SIRT 3广泛表达，但先前的全球SIRT 3敲除研究主要显示了心脏特异性表型。在这里，我们试图确定特异性敲除心肌细胞（SIRTcKO小鼠）中的SIRT 3如何在时间上影响心脏功能和代谢。小鼠心脏病理表现出年龄依赖性增加，10月龄小鼠表现出显著的收缩功能丧失、肥大和纤维化。虽然线粒体功能在10个月时保持不变，但蛋白质组学和代谢表型表明SIRT 3心脏对葡萄糖作为能量底物的依赖性增加。此外，SIRT 3cKO心脏中支链氨基酸显著增加，而mTOR活性不同时增加。重水标记实验表明，到3个月大时，SIRT 3cKO心脏中的蛋白质合成增加，促进肥大生长，并可能丧失蛋白质稳态。累积起来，这些数据显示SIRT 3的心肌细胞特异性损失导致具有加速老化表型的严重病理学。在线版本包含补充材料，可通过10.1007/s11357-022-00695-0获得。
SIRT3 is a longevity factor that acts as the primary deacetylase in mitochondria. Although ubiquitously expressed, previous global SIRT3 knockout studies have shown primarily a cardiac-specific phenotype. Here, we sought to determine how specifically knocking out SIRT3 in cardiomyocytes (SIRTcKO mice) temporally affects cardiac function and metabolism. Mice displayed an age-dependent increase in cardiac pathology, with 10-month-old mice exhibiting significant loss of systolic function, hypertrophy, and fibrosis. While mitochondrial function was maintained at 10 months, proteomics and metabolic phenotyping indicated SIRT3 hearts had increased reliance on glucose as an energy substrate. Additionally, there was a significant increase in branched-chain amino acids in SIRT3cKO hearts without concurrent increases in mTOR activity. Heavy water labeling experiments demonstrated that, by 3 months of age, there was an increase in protein synthesis that promoted hypertrophic growth with a potential loss of proteostasis in SIRT3cKO hearts. Cumulatively, these data show that the cardiomyocyte-specific loss of SIRT3 results in severe pathology with an accelerated aging phenotype. The online version contains supplementary material available at 10.1007/s11357-022-00695-0.
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影响因子：
8
作者：
Martin, Angelical S.;Abraham, Dennis M.;Hirschey, Matthew D.
通讯作者：
Hirschey, Matthew D.
DOI：
10.1093/function/zqab028
发表时间：
2021
期刊：
Function (Oxford, England)
影响因子：
--
作者：
Abbott CB;Lawrence MM;Kobak KA;Lopes EBP;Peelor FF 3rd;Donald EJ;Van Remmen H;Griffin TM;Miller BF
通讯作者：
Miller BF
影响因子：
8.8
作者：
Lavie, Julie;De Belvalet, Harmony;Benard, Giovanni
通讯作者：
Benard, Giovanni
DOI：
10.1002/jcsm.12772
发表时间：
2021-12
期刊：
Journal of cachexia, sarcopenia and muscle
影响因子：
--
作者：
Kobak KA;Lawrence MM;Pharaoh G;Borowik AK;Peelor FF 3rd;Shipman PD;Griffin TM;Van Remmen H;Miller BF
通讯作者：
Miller BF
影响因子：
5.6
作者：
Ingram, Donald K.;Roth, George S.
通讯作者：
Roth, George S.