Aging-associated dysfunction of Akt/protein kinase B: S-nitrosylation and acetaminophen intervention.
Aging-associated dysfunction of Akt/protein kinase B: S-nitrosylation and acetaminophen intervention.
复制标题
DOI：
10.1371/journal.pone.0006430
复制
发表时间：
2009-07-29
期刊：
影响因子：
3.7
通讯作者：
Blough ER
中科院分区：
文献类型：
--
作者：
Wu M;Katta A;Gadde MK;Liu H;Kakarla SK;Fannin J;Paturi S;Arvapalli RK;Rice KM;Wang Y;Blough ER
骨骼肌老化的特征是代谢和功能障碍的发生率增加，如果任其发展，可导致发病率和死亡率增加。这些疾病在骨骼肌老化中发展的潜在机制还不清楚。蛋白激酶B（Akt/PKB）是细胞代谢和存活的重要调节因子，但目前尚不清楚衰老肌肉是否表现出Akt功能的改变。在这里，我们报告了一种新的功能障碍的Akt在衰老的肌肉，这可能与S-亚硝基化，可以预防对乙酰氨基酚干预。与6个月和27个月的大鼠相比，Akt（Ser 473和Thr 308）的磷酸化水平在高龄大鼠（33个月）的比目鱼肌中更高。有趣的是，Akt磷酸化的这些增加与雷帕霉素（mTOR）磷酸化的哺乳动物靶蛋白减少相关，沿着胰岛素受体β（IR-β）、磷酸肌醇3-激酶（PI 3 K）、10号染色体上缺失的磷酸酶和张力蛋白同源物（PTEN）的水平降低以及磷酸肌醇依赖性激酶-1（PDK 1）（Ser 241）的磷酸化。体外Akt激酶测量和离体肌肉孵育实验表明，Akt激酶活性与年龄相关的损伤，这与Akt S-亚硝基化和诱导型一氧化氮合酶（iNOS）的增加有关。Akt功能的损害与肌细胞凋亡的增加、肌细胞大小的减少以及肌球蛋白和肌动蛋白的表达平行发生。通过对乙酰氨基酚（30 mg/kg体重/天）治疗老龄（27个月）动物6个月，减轻了这些年龄相关疾病。这些数据表明，Akt功能障碍和Akt的S-亚硝基化增加可能导致骨骼肌中的年龄相关疾病，对乙酰氨基酚可能有效治疗年龄相关的肌肉功能障碍。
Aged skeletal muscle is characterized by an increased incidence of metabolic and functional disorders, which if allowed to proceed unchecked can lead to increased morbidity and mortality. The mechanism(s) underlying the development of these disorders in aging skeletal muscle are not well understood. Protein kinase B (Akt/PKB) is an important regulator of cellular metabolism and survival, but it is unclear if aged muscle exhibits alterations in Akt function. Here we report a novel dysfunction of Akt in aging muscle, which may relate to S-nitrosylation and can be prevented by acetaminophen intervention. Compared to 6- and 27-month rats, the phosphorylation of Akt (Ser473 and Thr308) was higher in soleus muscles of very aged rats (33-months). Paradoxically, these increases in Akt phosphorylation were associated with diminished mammalian target of rapamycin (mTOR) phosphorylation, along with decreased levels of insulin receptor beta (IR-β), phosphoinositide 3-kinase (PI3K), phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and phosphorylation of phosphoinositide-dependent kinase-1 (PDK1) (Ser241). In vitro Akt kinase measurements and ex vivo muscle incubation experiments demonstrated age-related impairments of Akt kinase activity, which were associated with increases in Akt S-nitrosylation and inducible nitric oxide synthase (iNOS). Impairments in Akt function occurred parallel to increases in myocyte apoptosis and decreases in myocyte size and the expression of myosin and actin. These age-related disorders were attenuated by treating aged (27-month) animals with acetaminophen (30 mg/kg body weight/day) for 6-months. These data demonstrate that Akt dysfunction and increased S-nitrosylation of Akt may contribute to age-associated disorders in skeletal muscle and that acetaminophen may be efficacious for the treatment of age-related muscle dysfunction.
登录
查看更多内容
影响因子：
7.7
作者：
Carvalho, MA;Ueno, M;Saad, MJA
通讯作者：
Saad, MJA
影响因子：
7.7
作者：
Kurowski, TG;Lin, YS;Ruderman, NB
通讯作者：
Ruderman, NB
影响因子：
2.3
作者：
Lu, XM;Lu, M;Fischman, AJ
通讯作者：
Fischman, AJ
影响因子：
5
作者：
Pacheco, Maria E.;Beltran, Amada;Salaices, Mercedes
通讯作者：
Salaices, Mercedes
影响因子：
3.3
作者：
CAIOZZO, VJ;BAKER, MJ;BALDWIN, KM
通讯作者：
BALDWIN, KM