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ABSTRACT: Unlike muscles of young mice, skeletal muscles of old mice fail to recover completely following contraction-induced damage. The mechanisms by which this occurs are not fully understood. The ability of muscles of old mice to adapt following exercise by the increased production of heat shock proteins (HSPs) is blunted. Studies using transgenic mice have shown that this inability to produce HSPs has a major effect on muscle regeneration. Overexpression of HSP70 facilitated complete recovery of maximum tetanic force generation in muscles of old transgenic mice following contraction induced-damage in comparison with a deficit in muscles of old wild-type (WT) mice. We hypothesized that pharmacological induction of HSP70 in muscles of old WT mice would result in enhanced recovery from contraction-induced damage. A single dose of 40 mg/kg of 17-(allylamino)-17-demethoxygeldanamycin (17AAG) resulted in a significant increase in the HSP70 content of extensor digitorum longus muscles of adult C57BL6/J mice 3 days following treatment compared with vehicle-treated mice. Four weekly treatments of adult and old mice resulted in a two- to four-fold increase in muscle HSP70 content. Treatment of old mice with 17AAG at 3 days prior to and weekly for 4 weeks following a severely damaging contraction protocol resulted in enhanced recovery of force generation at 28 days postdamage compared with muscles of vehicle-treated mice. Data suggest that 17AAG overcomes the mechanism by which activation of the stress response fails in muscles of old mice and may have therapeutic benefit in the recovery following damage in muscles of older individuals.
Rejuvenation Research 01/2009; 11(6):1021-30. · 3.83 Impact Factor
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ABSTRACT: Skeletal muscle aging is characterized by atrophy, a deficit in specific force generation, increased susceptibility to injury, and incomplete recovery after severe injury. The ability of muscles of old mice to produce heat shock proteins (HSPs) in response to stress is severely diminished. Studies in our laboratory using HSP70 overexpressor mice demonstrated that lifelong overexpression of HSP70 in skeletal muscle provided protection against damage and facilitated successful recovery after damage in muscles of old mice. The mechanisms by which HSP70 provides this protection are unclear. Aging is associated with the accumulation of oxidation products, and it has been proposed that this may play a major role in age-related muscle dysfunction. Muscles of old wild-type (WT) mice demonstrated increased lipid peroxidation, decreased glutathione content, increased catalase and superoxide dismutase (SOD) activities, and an inability to activate nuclear factor (NF)-kappaB after contractions in comparison with adult WT mice. In contrast, levels of lipid peroxidation, glutathione content, and the activities of catalase and SOD in muscles of old HSP70 overexpressor mice were similar to adult mice and these muscles also maintained the ability to activate NF-kappaB after contractions. These data provide an explanation for the preservation of muscle function in old HSP70 overexpressor mice.
The FASEB Journal 08/2006; 20(9):1549-51. · 5.71 Impact Factor
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ABSTRACT: Alcoholic myopathy is a common pathology characterized by wasting due to reduced protein synthesis, although the mechanisms involved remain unclear. Women are particularly sensitive and malnutrition exacerbates the myopathy. This study aimed to address (i) whether long-term alcohol feeding alters expression of heat shock proteins (HSPs) in male and female rats; (ii) the effect of immediate alcohol dosing with or without raised levels of endogenous acetaldehyde; and (iii) the effect of starvation. To address this, (i) male and female rats were fed alcohol in the long-term (6-7 weeks as 35% of energy in a liquid diet) and compared to controls fed the same diet with isoenergetic glucose; (ii) male rats given an immediate bolus (75 mmol ethanol per kilogram body weight intraperitoneally) 2.5 hours before sacrifice and compared to controls given a dose of saline (with or without pretreatment with cyanamide-an acetaldehyde dehydrogenase inhibitor which raises endogenous acetaldehyde); (iii) male rats starved for 1 or 2 days then immediately dosed with alcohol. Protein levels of HSP 27, HSP 60, and HSP 70 were measured in muscles of male rats fed alcohol and pair-fed control rats by SDS-PAGE and Western blotting in study I. Levels of HSP 27, HSP 60, HSP 70, and HSP 90 mRNA were analyzed in hind limb skeletal muscle by reverse transcription-polymerase chain reaction with an endogenous internal standard, glyceraldehyde-3-phosphate-dehydrogenase. (i) Long-term alcohol dosage reduced HSP 27 in male rats but not in females, whereas HSP 90 mRNA increased in long-term alcohol-fed female rats but not in male rats. These changes were reflected by a similar trend in HSP protein content, although statistical significance was not achieved. (ii) There was no effect on any of the HSP mRNAs in rats dosed immediately with alcohol or in combination with cyanamide. (iii) Starvation per se for 2 days was associated with an increase in HSP 27 mRNA. Alcohol administration after 2 days starvation caused a blunting of the increased HSP 27 mRNA in starvation alone. This suggests that long-term alcohol exposure affects HSP gene expression and that this effect is moderated by sex and starvation. This may contribute to, or reflect, the biochemical lesion in alcoholic myopathy.
Metabolism 08/2006; 55(7):843-51. · 2.66 Impact Factor
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ABSTRACT: The ability of muscles of old mice to recover force generation following substantial damage is severely impaired, particularly during the late phase of regeneration. This inability to recover successfully may be associated with the attenuated ability of muscles of old mice to produce heat shock proteins (HSPs) in response to stress since muscles of old mice overexpressing HSP70 recover successfully following damage. The capacity of mature mammalian skeletal muscle to regenerate following damage is due to the presence of undifferentiated mononuclear myogenic precursor cells (satellite cells) at the periphery of mature skeletal muscle fibres. HSP expression is under the primary transcriptional control of heat shock factors 1 and 2 (HSF1 and HSF2). The aim of this study was to examine the expression of heat shock factors 1 and 2 by western blotting in mouse-derived C2C12 myoblasts as an experimental model system for investigating skeletal muscle regeneration. Data demonstrated that the HSF2 content of myotubes was significantly increased during the early stages of regeneration. In contrast, the HSF1 content of myotubes remained relatively low until late during regeneration. Thus, abnormal activation of HSF1 may play a role in the defective regeneration seen in muscles of old mice.
Experimental Gerontology 06/2006; 41(5):497-500. · 3.74 Impact Factor
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ABSTRACT: Dietary Se levels in the UK have fallen over the last 20 years and recent surveys indicate that average Se intakes are 30-40 microg/d, which is well below the current UK reference nutrient intake for adult men (75 microg/d) or women (60 microg/d). Functional consequences of this decline have not been recognised, although epidemiological data suggest it may contribute to increased risk of infections and incidence of some cancers. Previous data have indicated that biochemical changes in Se-dependent proteins occur in otherwise healthy UK subjects given small Se supplements. The current studies have focused on the effect of small Se supplements on the immune response since there is evidence of specific interactions between Se intake and viral replication, and since the potential anti-cancer effects of Se may be mediated by non-antioxidant effects of Se such as changes in immune function. Data indicate that subjects given small Se supplements (50 or 100 microg Se/d) have changes in the activity of Se-dependent enzymes and evidence of improved immune function and clearance of an administered live attenuated virus in the form of poliovirus vaccine. Responses of individual subjects to Se supplements are variable, and current work is evaluating potential explanations for this variability, including genetic variability and pre-existing Se status.
Proceedings of The Nutrition Society 12/2004; 63(4):513-7. · 2.77 Impact Factor
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ABSTRACT: Dietary selenium intakes in many countries, including the United Kingdom, are lower than international recommendations. No functional consequences of these lower intakes have been recognized, although experimental studies suggest that they might contribute to reduced immune function, increased cancer incidence, and increased susceptibility to viral disease.
The objective was to assess whether administration of small selenium supplements to otherwise healthy UK subjects leads to functional changes in immune status and the rates of clearance and mutation of a picornavirus: live attenuated polio vaccine.
Twenty-two adult UK subjects with relatively low plasma selenium concentrations (<1.2 micromol/L, approximately 60% of those screened) received 50 or 100 microg Se (as sodium selenite) or placebo daily for 15 wk in a double-blind study. All subjects received an oral live attenuated poliomyelitis vaccine after 6 wk and enriched stable (74)Se intravenously 3 wk later.
Selenium supplementation increased plasma selenium concentrations, the body exchangeable selenium pool (measured by using (74)Se), and lymphocyte phospholipid and cytosolic glutathione peroxidase activities. Selenium supplements augmented the cellular immune response through an increased production of interferon gamma and other cytokines, an earlier peak T cell proliferation, and an increase in T helper cells. Humoral immune responses were unaffected. Selenium-supplemented subjects also showed more rapid clearance of the poliovirus, and the poliovirus reverse transcriptase-polymerase chain reaction products recovered from the feces of the supplemented subjects contained a lower number of mutations.
The data indicate that these subjects had a functional selenium deficit with suboptimal immune status and a deficit in viral handling. They also suggest that the additional 100 microg Se/d may be insufficient to support optimal function.
American Journal of Clinical Nutrition 07/2004; 80(1):154-62. · 6.67 Impact Factor
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ABSTRACT: Much data indicate that overt selenium deficiency induces a number of pathologies in animals and humans. The effects of chronic marginal undernutrition of this element are unclear, although it has been argued that such subjects will be at increased risk of developing various cancers. The dietary intake of selenium in the UK has fallen over the last 25 years, although no functional consequences of this have been recognized. Recent data demonstrate that restoration of selenium intakes in UK subjects induces biochemical effects with increased activity of selenium-dependent enzymes. Whether such biochemical changes are associated with functional changes is currently unclear and the subject of current investigation.
Journal of Nutrition 06/2003; 133(5 Suppl 1):1557S-9S. · 3.92 Impact Factor
