Acute and Chronic Exercise in Animal Models

Exercise induces physiological cardiac growth and protects the heart against pathological remodeling. Recent work suggests exercise also enhances the heart's capacity for repair, which could be important for regenerative therapies. While microRNAs are important in certain cardiac pathologies, less is known about their functional roles in exercise-induced cardiac phenotypes. We profiled cardiac microRNA expression in two distinct models of exercise and found microRNA-222 (miR-222) was upregulated in both. Downstream miR-222 targets modulating cardiomyocyte phenotypes were identified, including HIPK1 and HMBOX1. Inhibition of miR-222 in vivo completely blocked cardiac and cardiomyocyte growth in response to exercise while reducing markers of cardiomyocyte proliferation. Importantly, mice with inducible cardiomyocyte miR-222 expression were resistant to adverse cardiac remodeling and dysfunction after ischemic injury. These studies implicate miR-222 as necessary for exercise-induced cardiomyocyte growth and proliferation in the adult mammalian heart and show that it is sufficient to protect the heart against adverse remodeling.

Oxidative stress has been implicated in the pathogenesis of cardiovascular diseases, including myocardial hypertrophy and infarction. Although impairment of antioxidant defense mechanisms has been thought to provoke oxidative stress-induced myocardial dysfunction, it has been difficult to clearly demonstrate. Nuclear erythroid 2 p45-related factor 2 (Nrf2) is a redox-sensitive, basic leucine zipper protein that regulates the transcription of several antioxidant genes. We previously reported that sustained activation of Nrf2 upregulates transcription of a number of endogenous antioxidants in the heart. Here, we show that acute exercise stress (AES) results in activation of Nrf2/ARE (antioxidant response element) signaling and subsequent enhancement of antioxidant defense pathways in wild-type (WT) mouse hearts, while oxidative stress, along with blunted defense mechanisms, was observed in Nrf2-/- mice. We also find that AES is associated with increased trans-activation of ARE-containing genes in exercised animals when compared to age-matched sedentary WT mice. However, enhanced oxidative stress in response to AES was observed in Nrf2-/- mice due to lower basal expression and marked attenuation of the transcriptional induction of several antioxidant genes. Thus, AES induces ROS and promotes Nrf2 function, but disruption of Nrf2 increases susceptibility of the myocardium to oxidative stress. Our findings suggest the basis for a nonpharmacological approach to activate Nrf2/ARE signaling, which might be a potential therapeutic target to protect the heart from oxidative stress-induced cardiovascular complications. Copyright © 2011 Elsevier Inc. All rights reserved.

Valid and reliable experimental models are essential to gain insight into the cellular and molecular mechanisms underlying the beneficial effects of exercise in prevention, treatment, and rehabilitation of lifestyle-related diseases. Studies with large changes, low variation, and reproducible training outcome require individualized training intensity, controlled by direct measurements of maximal oxygen uptake or heart rate. As this approach is expensive and time consuming, we discuss whether maximal treadmill running speed in a gradually increasing ramp protocol might be sufficient to control intensity without losing accuracy. Combined data from six studies of rats and mice from our lab demonstrated a close correlation between running speed and oxygen uptake. This relationship changed towards a steeper linear slope after endurance training, indicating improved work economy, that is, less oxygen was consumed at fixed submaximal running speeds. Maximal oxygen uptake increased 40-70% after high-intensity aerobic interval training in mice and rats. The speed at which oxygen uptake reached a plateau, increased in parallel with the change in maximal oxygen uptake during the training period. Although this suggests that running speed can be used to assess training intensity throughout a training program, the problem is to determine the exact relative intensity related to maximal oxygen uptake from running speed alone. We therefore suggest that directly measured oxygen uptake should be used to assess exercise intensity and optimize endurance training in rats and mice. Running speed may serve as a supplement to ensure this intensity.