Aging-Associated Dysfunction of Akt-Protein Kinase B: S-Nitrosylation and Acetaminophen InterventionReportar como inadecuado

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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 mechanisms 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.

Principal Findings

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.

Autor: Miaozong Wu, Anjaiah Katta, Murali K. Gadde, Hua Liu, Sunil K. Kakarla, Jacqueline Fannin, Satyanarayana Paturi, Ravi K. Arvapall



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