Rodent models for resolving extremes of exercise and health

The extremes of exercise capacity and health are considered a complex interplay between genes and the environment. In general, the study of animal models has proven critical for deep mechanistic exploration that provides guidance for focused and hypothesis driven discovery in humans. Hypotheses underlying molecular mechanisms of disease, and gene/tissue function can be tested in rodents in order to generate sufficient evidence to resolve and progress our understanding of human biology. Here we provide examples of three alternative uses of rodent models that have been applied successfully to advance knowledge that bridges our understanding of the connection between exercise capacity and health status. Firstly we review the strong association between exercise capacity and all-cause morbidity and mortality in humans through artificial selection on low and high exercise performance in the rat and the consequent generation of the "energy transfer hypothesis". Secondly we review specific transgenic and knock-out mouse models that replicate the human disease condition and performance. This includes human glycogen storage diseases (McArdle and Pompe) and α-actinin-3 deficiency. Together these rodent models provide an overview of the advancements of molecular knowledge required for clinical translation. Continued study of these models in conjunction with human association studies will be critical to resolving the complex gene-environment interplay linking exercise capacity, health, and disease.

Exercise as a polypill for chronic diseases

Exercise may be described as a polypill to prevent and/or treat almost every chronic disease, with obvious benefits such as its low cost and practical lack of adverse effects. Implementing physical activity interventions in public health is therefore a goal at the medical, social, and economic levels. This chapter describes the importance of health promotion through physical activity and discusses the impacts of exercise on the most prevalent chronic diseases, namely metabolic syndrome-related disorders, cardiovascular diseases, cancer, and Alzheimer's disease. For each of these chronic conditions, we discuss the epidemiological evidence supporting a beneficial role of exercise, provide guidelines for exercise prescription, and describe the biological mechanisms whereby exercise exerts its modulatory effects.

Gut microbiota modification: Another piece in the puzzle of the benefits of physical exercise in health?

Regular physical exercise provides many health benefits, protecting against the development of chronic diseases, and improving quality of life. Some of the mechanisms by which exercise provides these effects are the promotion of an anti-inflammatory state, reinforcement of the neuromuscular function, and activation of the hypothalamic–pituitary–adrenal (HPA) axis. Recently, it has been proposed that physical exercise is able to modify gut microbiota, and thus this could be another factor by which exercise promotes well-being, since gut microbiota appears to be closely related to health and disease. The purpose of this paper is to review the recent findings on gut microbiota modification by exercise, proposing several mechanisms by which physical exercise might cause changes in gut microbiota.

Active paraplegics are protected against exercise-induced oxidative damage through the induction of antioxidant enzymes

Exercise improves functional capacity in spinal cord injury (SCI). However, exhaustive exercise, especially when sporadic, is linked to the production of reactive oxygen species that may have a detrimental effect on SCI. We aimed to study the effect of a single bout of exhaustive exercise on systemic oxidative stress parameters and on the expression of antioxidant enzymes in individuals with paraplegia. The study was conducted in the Physical Therapy department and the Physical Education and Sports department of the University of Valencia. Sixteen paraplegic subjects were submitted to a graded exercise test (GET) until volitional exhaustion. They were divided into active or non-active groups. Blood samples were drawn immediately, 1 and 2 h after the GET. We determined plasma malondialdehyde (MDA) and protein carbonylation as markers of oxidative damage. Antioxidant gene expression (catalase and glutathione peroxidase-GPx) was determined in peripheral blood mononuclear cells. We found a significant increase in plasma MDA and protein carbonyls immediately after the GET (P<0.05). This increment correlated significantly with the lactate levels. Active paraplegics showed lower levels of exercise-induced oxidative damage (P<0.05) and higher exercise-induced catalase (P<0.01) and GPx (P<0.05) gene expression after the GET. These results suggest that exercise training may be useful in SCI patients to develop systemic antioxidant defenses that may protect them against exercise-induced oxidative damage.

Biological rationale for regular physical exercise as an effective intervention for the prevention and treatment of depressive disorders

Depression is a major medical and social problem. Here we review current body of knowledge on the benefits of exercise as an effective strategy for both the prevention and treatment of this condition. We also analyze the biological pathways involved in such potential benefits, which include changes in neurotrophic factors, oxidative stress and inflammation, telomere length, brain volume and microvessels, neurotransmitters or hormones. We also identify major caveats in this field of research: further studies are needed to identify which are the most appropriate types of exercise interventions (intensity, duration, or frequency) to treat and prevent depression.

Muscle signaling in exercise intolerance: Insights from the McArdle mouse model

We recently generated a knock-in mouse model (PYGM p.R50X/p.R50X) of McArdle disease (myophosphorylase deficiency). One mechanistic approach to unveil the molecular alterations caused by myophosphorylase deficiency, which is arguably the paradigm of 'exercise intolerance', is to compare the skeletal-muscle tissue of McArdle, heterozygous, and healthy (wild type (wt)) mice. We analyzed in quadriceps muscle of p.R50X/p.R50X (n=4), p.R50X/wt (n=6) and wt/wt mice (n=5) (all male, 8 wk-old) molecular markers of energy-sensing pathways, oxidative phosphorylation (OXPHOS) and autophagy/proteasome systems, oxidative damage and sarcoplamic reticulum (SR) Ca handling. We found a significant group effect for total AMPK (tAMPK) and ratio of phosphorylated (pAMPK)/tAMPK (P=0.012 and 0.033), with higher mean values in p.R50X/p.R50X mice vs. the other two groups. The absence of massive accumulation of ubiquitinated proteins, autophagosomes or lysosomes in p.R50X/p.R50X mice suggested no major alterations in autophagy/proteasome systems. Citrate synthase activity was lower in p.R50X/p.R50X mice vs. the other two groups (P=0.036) but no statistical effect existed for respiratory chain complexes. We found higher levels of 4-hydroxy-2-nonenal-modified proteins in p.R50X/p.R50X and p.R50X/wt mice compared with the wt/wt group (P=0.011). Sarco(endo)plasmic reticulum ATPase 1 (SERCA1) levels detected at 110kDa tended to be higher in p.R50X/p.R50X and p.R50X/wt mice compared with wt/wt animals (P=0.076), but their enzyme activity was normal. We also found an accumulation of phosphorylated SERCA1 in p.R50X/p.R50X animals. Myophosphorylase deficiency causes alterations in sensory energetic pathways together with some evidence of oxidative damage and alterations in Ca handling but with no major alterations in OXPHOS capacity or autophagy/ubiquitination pathways, which suggests that the muscle tissue of patients is likely to adapt overall favorably to exercise training interventions.

Effects of prior heavy exercise on V(over dot)O-2 kinetics during heavy exercise are related to changes in muscle activity

Burnley, M., Doust, J.H., Ball, D. and Jones, A.M. (2002) Effects of prior heavy exercise on VO2 kinetics during heavy exercise are related to changes in muscle activity. Journal of Applied Physiology 93, 167-174. RAE2008

Influence of blood donation on O-2 uptake on-kinetics, peak O-2 uptake and time to exhaustion during severe-intensity cycle exercise in humans

Thatcher, Rhys, et al., 'Influence of blood donation on O-2 uptake on-kinetics, peak O-2 uptake and time to exhaustion during severe-intensity cycle exercise in humans', Experimental Physiology (2006) 91(3) pp.499-509 RAE2008

Development and validation of a sport-specific exercise protocol for elite youth soccer players

Thatcher, Rhys, and Alan Batterham, 'Development and validation of a sport-specific exercise protocol for elite youth soccer players', Journal of Sports Medicine and Physical Fitness, (2004) 44(1) pp.15-22 RAE2008

The effect of 2 weeks vitamin C supplementation on immunoendocrine responses to 2.5 h cycling exercise in man

Davison G, Gleeson M, 2006. The effect of 2 weeks vitamin C supplementation on immunoendocrine responses to 2.5 h cycling exercise in man. European Journal of Applied Physiology 97(4): 454-461 RAE2008

Antioxidant supplementation and immunoendocrine responses to prolonged exercise

Davison, Glen, et al., 'Antioxidant supplementation and immunoendocrine responses to prolonged exercise', Medicine and Science in Sports and Exercise, (2007) 39(4) pp.645-652 RAE2008

'Psyching-up' enhances force production during the bench press exercise

Tod, D., Iredale, F., McGuigan, M., Strange, D., Gill, N. (2005). 'Psyching-up' enhances force production during the bench press exercise. Tod, 19 (3), 599-603. RAE2008

Time required for the restoration of normal heavy exercise Vo(2) kinetics following prior heavy exercise

Burnley, M., Doust, J. and Jones, A. (2006). Time required for the restoration of normal heavy exercise Vo(2) kinetics following prior heavy exercise. Journal of Applied Physiology. 101(5), pp.1320-1327 RAE2008

Influence of acute vitamin C and/or carbohydrate ingestion on hormonal, cytokine, and immune responses to prolonged exercise

Davison, G. and Gleeson, M. (2005). Influence of Acute Vitamin C and/or Carbohydrate Ingestion on Hormonal, Cytokine, and Immune Responses to Prolonged Exercise. International Journal of Sport Nutrition and Exercise Metabolism. 15(5), pp.465-479 RAE2008

The impact of short duration, high intensity exercise on cardiac troponin release

The aim of this study was to assess the appearance of cardiac troponins (cTnI and/or cTnT) after a short bout (30 s) of ‘all-out’ intense exercise and to determine the stability of any exercise-related cTnI release in response to repeated bouts of high intensity exercise separated by 7 days recovery. Eighteen apparently healthy, physically active, male university students completed two all-out 30 s cycle sprint, separated by 7 days. cTnI, blood lactate and catecholamine concentrations were measured before, immediately after and 24 h after each bout. Cycle performance, heart rate and blood pressure responses to exercise were also recorded. Cycle performance was modestly elevated in the second trial [6·5% increase in peak power output (PPO)]; there was no difference in the cardiovascular, lactate or catecholamine response to the two cycle trials. cTnI was not significantly elevated from baseline through recovery (Trial 1: 0·06 ± 0·04 ng ml−1, 0·05 ± 0·04 ng ml−1, 0·03 ± 0·02 ng ml−1; Trial 2: 0·02 ± 0·04 ng ml−1, 0·04 ± 0·03 ng ml−1, 0·05 ± 0·06 ng ml−1) in either trial. Very small within subject changes were not significantly correlated between the two trials (r = 0·06; P>0·05). Subsequently, short duration, high intensity exercise does not elicit a clinically relevant response in cTnI and any small alterations likely reflect the underlying biological variability of cTnI measurement within the participants.