Caroline S. Broome

Effect of lifelong overexpression of HSP70 in skeletal muscle on age-related oxidative stress and adaptation after nondamaging contractile activity

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)‐κB 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‐κB after contractions. These data provide an explanation for the preservation of muscle function in old HSP70 overexpressor mice.—Broome, C. S., Kayani, A. C., Palomero, J., Dillmann, W. H., Mestril, R., Jackson, M. J., McArdle, A. Effect of lifelong overexpression of HSP70 in skeletal muscle on age‐related oxidative stress and adaptation after nondamaging contractile activity. FASEB J. 20, E855–E860 (2006)

Enhanced Recovery from Contraction-Induced Damage in Skeletal Muscles of Old Mice Following Treatment with the Heat Shock Protein Inducer 17-(Allylamino)-17-Demethoxygeldanamycin

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.

Are there functional consequences of a reduction in selenium intake in UK subjects

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.

Marginal Dietary Selenium Intakes in the UK: Are There Functional Consequences?

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.

HSF expression in skeletal muscle during myogenesis: implications for failed regeneration in old mice.

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.

Heat shock factor activation in human muscles following a demanding intermittent exercise protocol is attenuated with hyperthermia

Aim:  The present study investigated whether increased activation of heat shock factors (HSF) following exercise relates primarily to the increased muscle temperature or to exercise in general.

Skeletal Muscle Aging

Aging is usually defined as “the progressive loss of function accompanied by decreasing fertility and increasing mortality with advancing age” [1]. It is a complex physiologic process involving morphologic and biochemical changes in single cells and in the whole organism. However, the aging process is as yet poorly understood. During the last few years, the effect of aging on skeletal muscle has been increasingly studied.