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Aging-associated dysfunction of Akt/protein kinase B: S-nitrosylation and acetaminophen intervention.

Wu M, Katta A, Gadde MK, Liu H, Kakarla SK, Fannin J, Paturi S, Arvapalli RK, Rice KM, Wang Y, Blough ER - PLoS ONE (2009)

Bottom Line: 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).Impairments in Akt function occurred parallel to increases in myocyte apoptosis and decreases in myocyte size and the expression of myosin and actin.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Marshall University, Huntington, West Virginia, United States of America.

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.

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-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.

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Related in: MedlinePlus

Akt hyper-phosphorylation does not result in increased phosphorylation of its downstream molecules.A. mTOR total protein and phosphorylation of mTOR at Ser2448 in 6-, 27-, 33-month control (33C) and acetaminophen-treated (33T) rats as determined by immunoblotting. B. GSK3β total protein and phosphorylated GSK3β (Ser9). Data are mean±SE (n = 4). abc: Groups without the same letter are significantly different (P<0.05).
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pone-0006430-g002: Akt hyper-phosphorylation does not result in increased phosphorylation of its downstream molecules.A. mTOR total protein and phosphorylation of mTOR at Ser2448 in 6-, 27-, 33-month control (33C) and acetaminophen-treated (33T) rats as determined by immunoblotting. B. GSK3β total protein and phosphorylated GSK3β (Ser9). Data are mean±SE (n = 4). abc: Groups without the same letter are significantly different (P<0.05).

Mentions: The abundance of phosphorylated mTOR (pmTOR) (Ser2448) and mTOR total protein in the very aged soleus were lower than that in the adult animals (−86.3% and −86.8%, respectively; P<0.05; Figure 2A), while chronic acetaminophen treatment restored the amount of phosphorylated and total mTOR to a level equivalent to that seen in 6- and 27-month old animals (P>0.05). The ratio of pmTOR/mTOR was not different between age-matched controls and acetaminophen-treated rats (P>0.05).


Aging-associated dysfunction of Akt/protein kinase B: S-nitrosylation and acetaminophen intervention.

Wu M, Katta A, Gadde MK, Liu H, Kakarla SK, Fannin J, Paturi S, Arvapalli RK, Rice KM, Wang Y, Blough ER - PLoS ONE (2009)

Akt hyper-phosphorylation does not result in increased phosphorylation of its downstream molecules.A. mTOR total protein and phosphorylation of mTOR at Ser2448 in 6-, 27-, 33-month control (33C) and acetaminophen-treated (33T) rats as determined by immunoblotting. B. GSK3β total protein and phosphorylated GSK3β (Ser9). Data are mean±SE (n = 4). abc: Groups without the same letter are significantly different (P<0.05).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2712760&req=5

pone-0006430-g002: Akt hyper-phosphorylation does not result in increased phosphorylation of its downstream molecules.A. mTOR total protein and phosphorylation of mTOR at Ser2448 in 6-, 27-, 33-month control (33C) and acetaminophen-treated (33T) rats as determined by immunoblotting. B. GSK3β total protein and phosphorylated GSK3β (Ser9). Data are mean±SE (n = 4). abc: Groups without the same letter are significantly different (P<0.05).
Mentions: The abundance of phosphorylated mTOR (pmTOR) (Ser2448) and mTOR total protein in the very aged soleus were lower than that in the adult animals (−86.3% and −86.8%, respectively; P<0.05; Figure 2A), while chronic acetaminophen treatment restored the amount of phosphorylated and total mTOR to a level equivalent to that seen in 6- and 27-month old animals (P>0.05). The ratio of pmTOR/mTOR was not different between age-matched controls and acetaminophen-treated rats (P>0.05).

Bottom Line: 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).Impairments in Akt function occurred parallel to increases in myocyte apoptosis and decreases in myocyte size and the expression of myosin and actin.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Marshall University, Huntington, West Virginia, United States of America.

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.

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-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.

Show MeSH
Related in: MedlinePlus