Acetaminophen prevents aging-associated hyperglycemia in aged rats: effect of aging-associated hyperactivation of p38-MAPK and ERK1/2
ABSTRACT 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.
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ABSTRACT: We and others previously reported that the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6 significantly accumulate with age in mouse lung, this is accompanied by elevated phosphorylation of p38. Here, we further investigate whether aging affects activation of p38 signalling and the inflammatory reaction after exposure to lipopolysaccharide (LPS) in lungs of mice in vivo and humans ex vivo. The data showed that activation of p38 peaked at 0.5h and then rapidly declined in young (2-month-old) mouse lung, after intranasal inhalation challenge with LPS. In contract, activation of p38 peaked at 24h and was sustained longer in aged (20-month-old) mice. As well as altered p38, activations of its upstream activator MKK and downstream substrate NF-κB were also changed in lungs of aged mice, which corresponded with the absent in the early phase but delayed increases in concentrations of TNF-α, IL-1β and IL-6. Consistent with the above observations in mice, similar patterns of p38 signalling also occurred in human lungs. Compared with younger lungs from adult-middle aged subjects, the activation of p38, MKK and NF-κB, as well as the production of pro-inflammatory cytokines were significantly increased in lungs of older subjects ex vivo. Exposure of human lung cells to LPS induced rapid activation of p38, MKK and NF-κB in these cells from adultmiddle aged subjects, but not older subjects, with increases in production of the pro-inflammatory cytokines. The LPS-induced rapid activation in lung cells from adult-middle aged subjects occurred as early as 0.25h after exposure, and then declined. Compared with adult-middle aged subjects, LPS exposure did not induce marked changes in the early phase, either in the activation of p38, MKK and NF-κB, or in the production of TNF-α, IL-1β or IL-6 in lung cells from older subjects. In contrast, these changes occurred relatively late, peaked at 16h and were sustained longer in lungs of older subjects. These data support the hypothesis that the sustained activation of the p38 signalling pathway at baseline and the absence in the early phase but delayed of p38 signalling pathway response to LPS in the elderly may play important roles in increased susceptibility of aged lungs to inflammatory injury.Experimental gerontology 05/2014; 57. DOI:10.1016/j.exger.2014.04.017 · 3.53 Impact Factor
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ABSTRACT: The purpose of this study was to determine if exercise and/or acetaminophen (APAP) alter collagen and cross-linking in the rat gastrocnemius, soleus, and heart. Male Wistar rats (n=50, 8-week-old) were divided into placebo (PLA) or APAP groups and sedentary (SED) or exercised (RUN) groups. APAP (200 mg•kg(-1)) was administered daily by oral gavage. Exercised groups ran on a treadmill 5 days•week(-1) for 8 weeks with progression to 60 minutes per day, 20 m•min(-1), and 8° incline. Tissues were assayed for collagen (hydroxyproline) and hydroxylyslpyridinoline (HP) and lysylpryidinoline (LP) cross-links by high performance liquid chromatography. Collagen content (μg collagen•mg dry weight(-1)) was greater in both the gastrocnemius (p<0.001, SED-PLA: 114±16 vs. 244±32) and soleus (p=0.005, SED-PLA: 51±7 vs. 99±27) of exercise animals. In contrast, collagen content was not greater in exercised animals treated with APAP (SED-APAP: 113±16 vs. 145±21) and soleus (SED-APAP: 55±8 vs. 57±10). HP cross-linking (mmol/mol collagen) in the gastrocnemius (SED-PLA: 126±28, RUN-PLA: 50±7, SED-APAP: 41±7, and RUN-APAP: 30±4) and soleus muscles (SED-PLA: 547±107, RUN-PLA: 318±92, SED-APAP: 247±64, and RUN-APAP: 120±17) was lower in exercised rats when compared to sedentary rats (p<0.05). Cross-linking was further reduced in animals treated with APAP (p<0.05). Neither heart collagen nor cross-linking was influenced by exercise or APAP (p>0.05). Our findings suggest that exercise and APAP have tissue specific effects on muscle collagen. Given the widespread use of APAP as an analgesic and antipyretic, further work in humans is warranted. Copyright © 2014, American Journal of Physiology - Regulatory, Integrative and Comparative Physiology.AJP Regulatory Integrative and Comparative Physiology 12/2014; 308(4):ajpregu.00374.2014. DOI:10.1152/ajpregu.00374.2014 · 3.53 Impact Factor
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ABSTRACT: The diminished ability of aged muscle to self-repair is a factor behind sarcopenia and contributes to muscle atrophy. Muscle repair depends on satellite cells whose pool size is diminished with aging. A reduction in Notch pathway activity may explain the age-related decrease in satellite cell proliferation, as this pathway has been implicated in satellite cell self-renewal. Skeletal muscle is a target of vitamin D which modulates muscle cell proliferation and differentiation in vitro and stimulates muscle regeneration in vivo. Vitamin D status is positively correlated to muscle strength/function, and elderly populations develop a vitamin D deficiency. The aim of this study was to evaluate how vitamin D deficiency induces skeletal muscle atrophy in old rats through a reduction in Notch pathway activity and proliferation potential in muscle.Nutrition & Metabolism 09/2014; 11(1):47. DOI:10.1186/1743-7075-11-47 · 3.36 Impact Factor