Acetaminophen prevents aging-associated hyperglycemia in aged rats: Effect of aging-associated hyperactivation of p38-MAPK and ERK1/2
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.
Available from: Mari Carmen Gomez-Cabrera
- "lysis mechanisms . In particular , this kinase seems to be required for muscle - specific ubiquitin ligase over - expression and increased ubiquitin - conjugating activity ( Li et al . , 2005 ) . Chronic hyperactivation state of p38 MAPK is observed in aged and inactive skeletal muscle ( Williamson , Gallagher , Harber , Hollon , & Trappe , 2003 ; Wu et al . , 2009 ) , suggesting that this kinase may be also involved in age - related muscle atrophy ( see Figure 1 ) ."
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ABSTRACT: Abstract Ageing causes a progressive decline in skeletal muscle mass that may lead to decreased strength and functionality. The term sarcopenia is especially used to characterise this geriatric syndrome. Numerous conditions and behaviours are considered to accelerate the progression of sarcopenia such as chronic diseases, malnutrition and physical inactivity. As people in modern countries are more and more sedentary, the impact of physical inactivity on the prevalence of sarcopenia might be more and more important in the future. In this review, we discuss how reactive oxygen species (ROS) could mediate the effects of lifelong inactivity in the onset and progression of age-related sarcopenia. Although the cellular mechanisms responsible for muscle ROS production are not necessarily the same, both inactivity and ageing are indeed known to increase basal ROS concentrations in skeletal muscle. New data and literature review are provided showing that chronic ROS overproduction induced by physical inactivity may exacerbate the activation of some redox-sensitive signalling pathways involved in age-related sarcopenia. We also address the scientific evidences implicating the role of ROS overproduction in the precocious failure of aged muscles to activate intracellular signalling responses to contractions.
Available from: PubMed Central
- "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). "
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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.
Available from: Kevin M Rice
- "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. "
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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.
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