The kinetics of oxygen uptake (V O 2 ) during the on-transient of moderate-intensity exercise have been shown to be slowed with ageing (Bell et al. 1999) and slower in untrained relative to trained adults (Chilibeck et al. 1996). Following 6 months of endurance exercise training, the kinetics of V O 2 in older men were appreciably accelerated (Babcock et al. 1994b) during cycle ergometer exercise, but it was unclear whether this acceleration was due to improved O 2 transport, increased mitochondrial capacity or a combination of both of these adaptations. In the present study we utilised a single-leg knee extension training model in order to gain information pertinent to the control of V O 2 kinetics in older men. This method of exercise allows use of Doppler technology to measure mean blood velocity (Shoemaker et al. 1994(Shoemaker et al. , 1996aRichardson et al. 1995Richardson et al. , 1999Richardson & Saltin, 1998). The knee extension exercise allows isolation of a specific muscle group (quadriceps), which appears to be particularly susceptible to age-related loss of oxidative capacity (Conley et al. 2000). As in the present study, the single-limb training model has been used to differentiate between effects due to O 2 transport and those due to O 2 utilisation and/or diffusion of O 2 from the capillaries to the mitochondria (Davies & Sargeant, 1975;Saltin et al. 1976;Henriksson, 1977;Thomas et al. 1981;Klausen et al. 1982;Hardman et al. 1987) although none of these studies have examined on-transient V O 2 kinetics. The advantage of using older subjects, with slow initial V O 2 kinetics, is that larger changes in V O 2 kinetics are elicited with training (Babcock et al. 1994b), and thus it is easier to determine the relative importance of oxygen delivery versus utilisation in determining V O 2 kinetics. Additionally, in studying ageing it is important to determine the mechanisms of the limitations to exercise, and thus potential interventions to stimulate specific adaptations.If, following single-leg knee extension training, the kinetics of V O 2 were accelerated in the untrained (as well as the trained) leg, then this would imply that the acceleration is due to an adaptation to compensate for a limitation in O 2 delivery (Hughson et al. 1996). However, if V O 2 kinetics were accelerated in the trained leg only, then these data would support the possibility of improved blood flow to the exercising limb, enhanced diffusion of O 2 or improvement in metabolic function (Grassi et al. 1996). We measured mean blood velocity (MBV) in the femoral artery as an indicator of

Both protein kinase C (PKC) activation and Hsp70 expression have been shown to be key components for exercise-mediated myocardial protection during ischemia-reperfusion injury. Given that Hsp70 has been shown to undergo inducible phosphorylation in striated muscle and liver, we hypothesized that PKC may regulate myocardial Hsp70 function and subsequent exercise-conferred cardioprotection through this phosphorylation. Hence, acute exercise of male Sprague-Dawley rats (30 m/min for 60 min at 2% grade) was employed to assess the role of PKC and its selected isoforms in phosphorylation of Hsp70 and protection of the myocardium during ischemia-reperfusion injury. It was observed that administration of the PKC inhibitor chelerythrine chloride (5 mg/kg) suppressed the activation of three exercise-induced PKC isoforms (PKCα, PKCδ, and PKCɛ) and attenuated the exercisemediated reduction of myocardial infarct size during ischemia-reperfusion injury. While this study also demonstrated that exercise led to an alteration in the phosphorylation status of Hsp70, this posttranslational modification appeared to be dissociated from PKC activation, as exercise-induced phosphorylation of Hsp70 was unchanged following inhibition of PKC. Taken together, these results indicate that selected isoforms of PKC play an important role in exercise-mediated protection of the myocardium during ischemia-reperfusion injury. However, exerciseinduced phosphorylation of Hsp70 does not appear to be a mechanism by which PKC induces this cardioprotective effect.

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An issue central to understanding the biological benefits associated with regular exercise training is to elucidate the intracellular mechanisms governing exercise-conferred cardioprotection. Heat shock proteins (HSPs), most notably the inducible 70-kDa HSP family member Hsp70, are believed to participate in the protection of the myocardium during cardiovascular stress. Following acute exercise, activation of PKA mediates the suppression of an intermediary protein kinase, ERK1/2, which phosphorylates and suppresses the activation of the heat shock transcription factor 1 (HSF1). However, following exercise training, ERK1/2 has been reported to regulate the transcriptional activation of several genes involved in cell growth and proliferation and has been shown to be associated with training-mediated myocardial hypertrophy. The present project examined the transcriptional activation of hsp70 gene expression in acutely exercised (60 min at 30 m/min) naïve sedentary and aerobically trained (8 wk, low intensity) male Sprague-Dawley rats. Following acute exercise stress, no significant differences were demonstrated in the expression of myocardial Hsp70 mRNA and activation of PKA between sedentary and trained animals. However, trained animals elicited expression of the hsp70 gene (P < 0.05) in the presence of elevated ERK1/2 activation. Given the association of ERK1/2 and the suppression of hsp70 gene expression following acute exercise in naïve sedentary rats, these results suggest that training results in adaptations that allow for the simultaneous initiation of both proliferative and protective responses. While it is unclear what factors are associated with this training-related shift, increases in HSF1 DNA binding affinity (P < 0.05) and posttranscriptional modifications of the Hsp70 transcript are suggested.

Noble EG. Exercise training improves myocardial tolerance to ischemia in male but not in female rats. Am J Physiol Regul Integr Comp Physiol 293: R363-R371, 2007. First published May 16, 2007; doi:10.1152/ajpregu.00363.2006.-Acute exercise increases myocardial tolerance to ischemia-reperfusion (I-R) injury in male but not in female rat hearts, possibly due to a decreased heat shock protein 70 (Hsp70) response in the female hearts. This study examined whether repetitive exercise training would increase Hsp70 and myocardial tolerance to I-R injury in female rat hearts. Adaptations in myocardial manganese superoxide dismutase (MnSOD) and endothelial nitric oxide synthase (eNOS) were also assessed. Ten-week old male (M) and female (F) Sprague-Dawley rats (n ϭ 40 total) exercise-trained for 14 wk; the last 8 wk consisted of running 1 h at 30 m/min (2% incline), 5 days/wk. Following training, left ventricle mechanical function (LVMF) was monitored for 30 min of reperfusion following 30 min of global ischemia (Langendorff procedure). Myocardial Hsp70 content was not different in M and F control groups, while increases were observed in both trained groups (M greater than F; P Ͻ 0.05). Although MnSOD content did not differ between groups, endothelial nitric oxide synthase (eNOS) levels were decreased in F, with no change in M, following training (P Ͻ 0.05). Hearts from control F demonstrated a greater recuperation of all indices of LVMF following I-R compared with control M hearts (P Ͻ 0.05). Hearts of trained M exhibited improved recovery of LVMF (left ventricular diastolic pressure, left ventrcular end-diastolic pressure, ϩdP/dt, ϪdP/ dt) during reperfusion compared with control M hearts (P Ͻ 0.05). In contrast, hearts of trained F did not show any change in recovery from I-R. Hence, exercise training is more beneficial to M than F in improving myocardial function following I-R injury.heat shock proteins; sex; Langendorff THE MAJOR INDUCIBLE HEAT SHOCK protein, heat shock protein 70 (Hsp70), has been shown to be a cardioprotective agent. Currie et al. (10) were the first to show that whole body hyperthermia rendered the rodent myocardium more tolerant to ischemiareperfusion (I-R) injury. These researchers later noted that the induction of Hsp70 coincided with the cardioprotection afforded by hyperthermia, although no direct relationship was established (19). Subsequent research using transgenic models of Hsp70 overexpression has provided direct evidence for the involvement of Hsp70 in cardioprotection (24,34,41).It is widely accepted that exercise can lead to beneficial cardiovascular adaptations. Although its precise mechanisms on heart health have not been fully defined, chronic exercise is believed to influence a number of parameters, including improving blood-lipid profile, reducing sympathetic tone and enhancing endogenous defense systems [for a review, see Erikssen (12)]. Regarding endogenous defense mechanisms, several studies have reported augmented Hsp70 content and altered antioxidant status in the myocar...