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.

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.

Antidepressant effects of exercise: a role for the adiponectin-PGC-1α-kynurenine triad?

It is well-recognized that exercise improves mental health, e.g., by decreasing depressive behaviors, improving hippocampal-dependent learning and neurogenesis, and increasing dendritic plasticity. Yet how exercise influences the brain at the molecular level is not clearly understood. Yau et al recently reported that the antidepressant effects of physical exercise are mainly mediated by adiponectin, an adipocyte-secreted hormone ('adipocytokine') with neuroprotective effects at the central nervous system level (Yau et al., 2014). This article is protected by copyright. All rights reserved

Exercise for the management of type 2 diabetes: A review of the evidence

The aim is to critically review the more relevant evidence on the interrelationships between exercise and metabolic outcomes. The research questions addressed in the recent specific literature with the most relevant randomized controlled trials, meta-analysis and cohort studies are presented in three domains: aerobic exercise, resistance exercise, combined aerobic and resistance exercise. From this review appear that the effects of aerobic exercise are well established, and interventions with more vigorous aerobic exercise programs resulted in greater reductions in HbA1c, greater increase in VO2max and greater increase in insulin sensitivity. Considering the available evidence, it appears that resistance training could be an effective intervention to help glycemic control, especially considering that the effects of this form of intervention are comparable with what reported with aerobic exercise. Less studies have investigated whether combined resistance and aerobic training offers a synergistic and incremental effect on glycemic control; however, from the available evidences appear that combined exercise training seems to determine additional change in HbA1c that can be seen significant if compared with aerobic training alone and resistance training alone.

Exercise training can induce cardiac autophagy at end-stage chronic conditions: Insights from a graft-versus-host-disease mouse model

Chronic graft-versus-host disease (cGVHD) is a frequent cause of morbimortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and severely compromises patients' physical capacity. Despite the aggressive nature of the disease, aerobic exercise training can positively impact survival as well as clinical and functional parameters. We analyzed potential mechanisms underlying the recently reported cardiac function improvement in an exercise-trained cGVHD murine model receiving lethal total body irradiation and immunosuppressant treatment (Fiuza-Luces et al., 2013. Med Sci Sports Exerc 45, 1703-1711). We hypothesized that a cellular quality-control mechanism that is receiving growing attention in biomedicine, autophagy, was involved in such improvement. Our results suggest that exercise training elicits a positive autophagic adaptation in the myocardium that may help preserve cardiac function even at the end-stage of a devastating disease like cGVHD. These preliminary findings might provide new insights into the cardiac exercise benefits in chronic/debilitating conditions.

Cancer is essentially due to bad luck...but not so much if you don’t exercise or are overweight

2.241 JCR (2015) Q3, 140/213 Oncology, 45/80 Nutrition & dietetics

Phenotype consequences of myophosphorylase dysfunction: insights from the McArdle mouse model

McArdle disease, caused by inherited deficiency of the enzyme muscle glycogen phosphorylase (GP-MM), is arguably the paradigm of exercise intolerance. The recent knock-in (p.R50X/p.R50X) mouse disease model allows an investigation of the phenotypic consequences of muscle glycogen unavailability and the physiopathology of exercise intolerance. We analysed, in 2-month-old mice [wild-type (wt/wt), heterozygous (p.R50X/wt) and p.R50X/p.R50X)], maximal endurance exercise capacity and the molecular consequences of an absence of GP-MM in the main glycogen metabolism regulatory enzymes: glycogen synthase, glycogen branching enzyme and glycogen debranching enzyme, as well as glycogen content in slow-twitch (soleus), intermediate (gastrocnemius) and glycolytic/fast-twitch (extensor digitorum longus; EDL) muscles.

McArdle disease: a unique study model in sports medicine

McArdle disease is arguably the paradigm of exercise intolerance in humans. This disorder is caused by inherited deficiency of myophosphorylase, the enzyme isoform that initiates glycogen breakdown in skeletal muscles. Because patients are unable to obtain energy from their muscle glycogen stores, this disease provides an interesting model of study for exercise physiologists, allowing insight to be gained into the understanding of glycogen-dependent muscle functions. Of special interest in the field of muscle physiology and sports medicine are also some specific (if not unique) characteristics of this disorder, such as the so-called 'second wind' phenomenon, the frequent exercise-induced rhabdomyolysis and myoglobinuria episodes suffered by patients (with muscle damage also occurring under basal conditions), or the early appearance of fatigue and contractures, among others. In this article we review the main pathophysiological features of this disorder leading to exercise intolerance as well as the currently available therapeutic possibilities.

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.

Blood and urinary abnormalities induced during and after 24-hour continuous running: A case report

In this reported clinical case, a healthy and well-trained male subject [aged 37 years, maximal oxygen uptake (V[Combining Dot Above]O2max) 64 mL·kg·min] ran for 23 hours and 35 minutes covering 160 km (6.7 km/h average running speed). The analysis of hematological and biochemical parameters 3 days before the event, just after termination of exercise, and after 24 and 48 hours of recovery revealed important changes on muscle and liver function, and hemolysis. The analysis of urine sediments showed an increment of red and white blood cells filtrations, compatible with transient nephritis. After 48 hours, most of these alterations were recovered. Physicians and health professionals who monitor such athletic events should be aware that these athletes could exhibit transient symptoms compatible with severe pathologies and diseases, although the genesis of these blood and urinary abnormalities are attributable to transient physiological adaptations rather to pathological status.

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.