Aging-related hyperglycemia is associated with increased oxidative stress and diminished muscle glucose transporter-4 (Glut4) that may be regulated, at least in part, by the mitogen-activated protein kinases (MAPK).
To test the possibility that aging-related hyperglycemia can be prevented by pharmacological manipulation of MAPK hyperactivation, aged (27-month old) Fischer 344/NNiaHSD x Brown Norway/BiNia F1 (F344BN) rats were administered acetaminophen (30 mg/kg body weight/day) for 6 months in drinking water.
Hepatic histopathology, serum aspartate aminotransferase and alanine aminotransferase analyses suggested that chronic acetaminophen did not cause hepatotoxicity. Compared with adult (6-month) and aged (27-month) rats, very aged rats (33-month) had higher levels of blood glucose, phosphorylation of soleus p38-MAPK and extracellular-regulated kinase 1/2 (ERK1/2), superoxide and oxidatively modified proteins (p<0.05), and these changes were associated with decreased soleus Glut4 protein abundance (p<0.05). Chronic acetaminophen treatment attenuated age-associated increase in blood glucose by 61.3% (p<0.05) and increased soleus Glut4 protein by 157.2% (p<0.05). These changes were accompanied by diminished superoxide levels, decrease in oxidatively modified proteins (-60.8%; p<0.05) and reduced p38-MAPK and ERK1/2 hyperactivation (-50.4% and -35.4%, respectively; p<0.05).
These results suggest that acetaminophen may be useful for the treatment of age-associated hyperglycemia.
"It has been shown that prolonged mitogen activated protein kinase (MAPK) activation is associated with decreased Glut4 expression (Fujishiro et al., 2001; Carlson et al., 2003) and Glut4 translocation in response to insulin (Bandyopadhyay et al., 2001; Izawa et al., 2005; D’Alessandris et al., 2007). Interestingly, works done by Wu et al. (2009a) showed that acetaminophen treatment could normalize the marked increases in p38- and ERK–MAPK activation seen in aged muscle. Taken together, these findings suggests that acetaminophen might function to improve blood glucose levels by employing multiple mechanisms including decreases in intracellular ROS levels, diminished aging-associated MAPK hyperphosphorylation and by increasing muscle Glut4 expression (Wu et al., 2009a). "
[Show abstract][Hide abstract] ABSTRACT: Acetaminophen, also known as APAP or paracetamol, is one of the most widely used analgesics (pain reliever) and antipyretics (fever reducer). According to the U.S. Food and Drug Administration, currently there are 235 approved prescription and over-the-counter drug products containing acetaminophen as an active ingredient. When used as directed, acetaminophen is very safe and effective; however when taken in excess or ingested with alcohol hepatotoxicity and irreversible liver damage can arise. In addition to well known use pain relief and fever reduction, recent laboratory and pre-clinical studies have demonstrated that acetaminophen may also have beneficial effects on blood glucose levels, skeletal muscle function, and potential use as cardioprotective and neuroprotective agents. Extensive laboratory and pre-clinical studies have revealed that these off-label applications may be derived from the ability of acetaminophen to function as an antioxidant. Herein, we will highlight these novel applications of acetaminophen, and attempt, where possible, to highlight how these findings may lead to new directions of inquiry and clinical relevance of other disorders.
Frontiers in Pharmacology 11/2011; 2:72. DOI:10.3389/fphar.2011.00072 · 3.80 Impact Factor
"Nonetheless, compared to that observed in the young/adult animal, the basal phosphorylation of MAPK is higher in aged muscle from both human and animals (Williamson et al., 2003; Mylabathula et al., 2006; Wu et al., 2009a). The increase in MAPK basal phosphorylation appears to be associated with age-associated increases in oxidative stress (Hollander et al., 2000; Ji, 2002; Wu et al., 2009a), as interventions aimed to diminish ROS can effectively normalize age-associated MAPK hyper-phosphorylation (Wu et al., 2009a). It is possible that age-related muscle " stress " may impair the ability of aging skeletal muscle to sense and adapt to mechanical stimuli, resulting in dysregulation of the MAPK signaling pathways. "
[Show abstract][Hide abstract] ABSTRACT: Aging is becoming a critical heath care issue and a burgeoning economic burden on society. Mechanotransduction is the ability of the cell to sense, process, and respond to mechanical stimuli and is an important regulator of physiologic function that has been found to play a role in regulating gene expression, protein synthesis, cell differentiation, tissue growth, and most recently, the pathophysiology of disease. Here we will review some of the recent findings of this field and attempt, where possible, to present changes in mechanotransduction that are associated with the aging process in several selected physiological systems, including musculoskeletal, cardiovascular, neuronal, respiratory systems and skin.
Ageing research reviews 11/2009; 10(1):1-15. DOI:10.1016/j.arr.2009.11.002 · 4.94 Impact Factor
"Although it is unclear why aging might increase iNOS levels, other reports have suggested that increased extracellular glucose levels can induce iNOS expression , . A previous study by our laboratory demonstrated that age-associated hyperglycemia and decreases in muscle glucose transporter-4 (Glut4) can be reversed by acetaminophen intervention , while other work using cultured cell has shown that acetaminophen can directly inhibit NO production and iNOS expression through its ability to diminish NF-kappaB binding to the iNOS gene promoter . Consistent with these findings, we show that age-associated increases in iNOS expression were reversed after acetaminophen treatment, and further that this decrease in iNOS expression coincided with decreases in the amount of S-nitrosylated Akt (Figure 5A). "
[Show abstract][Hide abstract] ABSTRACT: 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-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.
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.
PLoS ONE 02/2009; 4(7):e6430. DOI:10.1371/journal.pone.0006430 · 3.23 Impact Factor
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