title: Aging-associated dysfunction of Akt/protein kinase B: S-nitrosylation and acetaminophen intervention.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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-beta), 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biological Sciences, Marshall University, Huntington, West Virginia, United States of America.
authors.forename: Miaozong
authors.initials: M
authors.lastname: Wu
authors.forename: Anjaiah
authors.initials: A
authors.lastname: Katta
authors.forename: Murali K
authors.initials: MK
authors.lastname: Gadde
authors.forename: Hua
authors.initials: H
authors.lastname: Liu
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Kakarla
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Fannin
authors.forename: Satyanarayana
authors.initials: S
authors.lastname: Paturi
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Arvapalli
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Rice
authors.forename: Yeling
authors.initials: Y
authors.lastname: Wang
authors.forename: Eric R
authors.initials: ER
authors.lastname: Blough
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology*; D000199:Actins / Q000378:metabolism; D000375:Aging / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D018482:Muscle, Skeletal / Q000166:cytology / Q000201:enzymology; D009218:Myosins / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009603:Nitroso Compounds / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats
chemical_list: D000199:Actins; D009603:Nitroso Compounds; D000082:Acetaminophen; D052247:Nitric Oxide Synthase Type II; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat; D009218:Myosins