Exercise and Sports Genetics - Assignment Example

Title: The association of Peroxisome Proliferator-Activated Receptor-δ with physical performance Introduction: The various health benefits from physical exercise are well documented such that physical exercise is now an integral part of lifestyle interventions that aim to control or prevent lifestyle diseases like diabetes, hypertension and cardiac disorders. Exercise produces changes in the metabolism, in the micro and macro circulation, changes in oxidation and changes in the musculature that create various benefits. Reduction in all cause mortality and risk factors for cardiac diseases and diabetes is a well recognized benefit of regular exercise (Kesaniemi YK,et al; 2001). Lifestyle diseases are important from a global perspective. Current estimates from the WHO suggest that lifestyle diseases will be the single largest contributor to mortality worldwide (as high as 73% of all mortality may be related to some lifestyle disease. Regular physical exercise is an important part of interventions targeting lifestyle diseases. Optimal benefits from such interventions are possible only if exercise regimes are customized to the needs of the individuals and are based on an understanding of the differing physiological responses to exercise. A “one shoe size fits all” approach is not possible for an exercise regime. Different people need different exercise regimes to derive optimal benefits without harm. Additionally, different people may respond differently to the same exercise regime. Thus, a light workout for one person may actually be a heavy workout for another person even if they are following the same exercise routine. The physiological response of various systems of the body may differ between individuals; this variability may be related to genetic factors (Bouchard C, Rankinen T, 2001). Peroxisome Proliferator-Activated Receptors (PPARs) are nuclear receptors with several gene modulation functions including those of lipid metabolism. Peroxisome proliferator-activated receptor-δ (PPARD), one of the PPARs, promotes fatty acid oxidation in adipocytes and skeletal muscle cells, potentially regulates muscle fiber, and impacts on endurance, and play a central role in blood lipid metabolism. These features of PPARD suggest that it may play an important role in determining exercise tolerance and physical performance through its ability to modulate or modify several physiologic functions. Fatty acids and their metabolites are natural ligands to PPARs that activate PPAR-. Reverse cholesterol transport has been promoted through the activation of PPAR- with a synthetic compound. This has increased the serum HDL level in mice and monkeys. PPARD also reduces the levels of LDL and triglycerides. There is an increased expression of genes that are involved in fatty acid oxidation and energy uncoupling in skeletal muscle. The subsequent dissipation of energy that results from this fatty acid oxidation and energy uncoupling lead to reduced adiposity and play protective role against diet-induced obesity. These changes also play a part in modulating insulin sensitivity by improving insulin sensitivity with consequent benefits on obesity and adiposity. PPARD, which has been mapped to 6p21.2-p21.1, has 11 exons and spans 35 kbp. Nine SNPs of PPARD have been reported and these polymorphisms have been associated with fasting plasma glucose levels and BMI. In mice, over expression of an activated form of PPARD coordinates the responses of oxidative enzymes, mitochondrial biogenesis, and type 1 muscle fiber contractile proteins in mice. PPARD is a crucial determinant of cardiac fatty acid oxidation in mice that maintains energy balance and normal cardiac function indicating that PPARD and its ligands may play an important role in the regulation of muscle fiber type distribution, endurance performance, and normal cardiac function. The current review focuses on the potential influence of PPARD on physical performance. These influences may be modulated through changes in mitochondrial activity that influence oxidative capacity and trainability, changes in the lipid metabolism pathways, energy uncoupling, changes in the insulin response- sensitivity and resistance, changes in the utilization and uptake of glucose by skeletal muscles, changes in body composition including adiposity and relative muscle mass. PPARs and the Heart The ability of the heart to respond to physical activities or stress is important. The heart pumps and circulates blood that plays a role in metabolism at many levels besides the transport of necessary oxygen and glucose that is necessary for tissues to formulate appropriate responses. Endurance in sports and other physical activities is related in some part to the ability of the heart to respond to such stress. The heart muscles or myocytes use fatty acids and glucose as energy substrates. Fatty acid oxidation is responsible for the creation of 60-90% of the ATP of the heart while the remaining is derived from glucose oxidation (Huss and Kelly, 2004). The heart, however, does not store lipids in a significant amount demonstrating the importance of cellular uptake of fatty acids, their oxidation and the genetic mechanism that may modulate or influence these metabolic processes (Huss and Kelly, 2004). Experiments on mice that deleted the gene regulating the creation of PPAR beta have shown a decrease in the creation of brown and white adipose tissue (Huss and Kelly, 2004). Research done by Gilde et al (2003) determined that PPAR alpha and beta/delta, but not gamma, are involved in cardiac lipid metabolism. In their experiments, they used rat cardiac cells as well as embryonic rat heart-derived H9c2 cells. Several cultures were grown with specific ligands for each PPAR. Appropriate genetic testing and protein extraction techniques were performed to determine that cardiomyocytes had higher levels of the synthetase ACS, the long-chain acetyl-coenzyme A dehydrogenase (LCAD) and the uncoupling protein UCP-2 (enzymes associated with lipid metabolism), rather than the glucose transporter GLUT4 and the glycolytic enzyme HKII, which were related to the metabolism of glucose (Glide et al.). PPAR alpha was detected only in myocytes while PPAR beta/delta was detected in both grown myocytes and embryonic cells. The researchers concluded that PPAR alpha and beta/delta are strongly involved in lipid metabolism; PPAR beta/delta had more influential roles during the developing stages of the cardiac muscles. It was also determined that PPAR beta/delta plays some role in the pathway of lipid metabolism suggesting that PPAR beta/delta may improve the uptake and metabolism of lipids and consequently, physical performance. Skeletal muscles and PPAR delta The strength of the heart muscle is not the only element of physical exercise that should be considered. The utilization of carbohydrates and lipids by skeletal muscles is also important. Skeletal tissue consists of myofibres that differs in their contractual and metabolic properties. These include the oxidative slow-twitch (type I), mixed oxidative/glycolytic fast-twitch (type IIA), and glycolytic fast-twitch (type IIB) forms. Skeletal muscle has the power to adapt to regulate the composition of slow-and fast-twitch myofibres. An increased amount of slow and fast twitch myofibres will increase the fatigue level of skeletal muscle which is useful for endurance sport. An increase of myofibres of skeletal muscle will decrease the obesity induced factors and that will also increase the endurance in sports athletics. Dressel et al. performed an experiment by using several agonists in order to determine their effects on PPAR ß. By using the agonist GW501516, they promoted several processes of lipid metabolism, namely preferential lipid utilization, ß-oxidation, cholesterol efflux, and energy uncoupling. They determined that treating skeletal muscles with the same agonist led to an increase of specific efflux of apolipoprotein A1 of cholesterol. The role of PPARD in losing weight and controlling obesity is important as these will elad to an increase in the relative muscle volume. It was determined that PPARD is involved in muscle remodeling (Soriano et al, 2006.). Experiments done on animals have shown less adipose tissue and higher levels of enzymes included in oxidation of lipids. It was also proven that exercise increases the number of PPARD delta, and that it may represent a natural response, just like the increase in muscle mass after prolonged training. Animals with a higher amount of PPARD showed higher physical activity and low intake of lipids, leading to the conclusion that PPARD delta could be regulated through nutrition (Soriano et al, 2006.) An important correlation between the increase of PPARD and interleukin-6 was also established, as the increase of the one leads to the increase of the other. This may establish an important link between the development of new muscle fibers and interleukin-6, making muscles more capable to metabolize glucose and lipids (Soriano et al, 2006.) SNPs in PPARD have been shown to be significantly associated with whole body insulin sensitivity. SNPs in PPARD primarily affect insulin sensitivity by modifying the skeletal muscle glucose uptake. In hyperinsulinemic conditions, the skeletal muscles utilize most of the glucose with adipose tissue glucose uptake contributing only modestly to whole-body insulin sensitivity. PPARD activating agonists has been shown to promote lipid oxidation and energy uncoupling in skeletal muscle. SNPs of PPARD possibly alter gene transcription, affecting lipid oxidation, energy uncoupling, and insulin sensitivity in humans similarly to animal models. Role of PPARD in Organs Organs Role Artery Increased HDL Cholesterol Liver Decreased Glucose output and increased Pentose Phosphate shunt Heart Increased Contractile function and Increased fatty acid increased transport and oxidation. Muscle Increased transport, oxidation, endurance capacity, increased slow-twitch fibres, increased thermo genesis. Adipose Tissue Prevention of obesity, increased transportation, increased oxidation and increased thermogenesis. PPARD and aerobic exercise PPARD plays an important role in mitochondrial function in animals and in vitro. Activation of PPARD is associated with increased expression of genes involved in lipid uptake and fatty acid oxidation and uncoupling proteins effectively uncoupling oxidation from the production of energy- this process is a strong determinant of aerobic fitness (Russell et al, 2002). Aerobic training with dietary restriction in sedentary obese adults is reported to result in enlargement of mitochondria, increase in the mitochondrial content in skeletal muscle and improvements in insulin sensitivity. Individual differences in such benefits may be explained by mitochondrial dysfunction and less type I fibers in skeletal muscle of these individuals leading to lower oxidative capacity and resulting in less energy transduction; these changes may be hereditary in nature. A study by Stefan et al, (2007), provided evidence for the association of single nucleotide polymorphisms (SNPs) of PPARD with the effectiveness of aerobic exercise training. They also confirmed that a SNP of PPARD is a determinant of mitochondrial function in vitro. The SNP rs2267668 in PPARD was associated with aerobic physical fitness, determined by the IAT and VO2 peak cycle and with estimated mitochondrial function. A pronounced effect on IAT was displayed by a haplotype carrying the minor allele at this locus. The effects were independent of the Gly482Ser SNP in PPARGC1A, supporting the role of the SNP rs2267668 in PPARD in the modulation of aerobic fitness. This study provided evidence for rs2267668 G/A SNP in PPARD and the Gly482Ser SNP in PPARGC1A having an independent and additive impact on the effectiveness of aerobic exercise training to increase aerobic physical fitness and insulin sensitivity. The lack of direct ATP Generation measures is a limitation of the study. Additionally, skeletal muscle donors were younger (mean age 26 yr), compared with the participants who underwent the lifestyle intervention (mean age 45 yr), although this is not expected to influence the results too much. PPARD and Changes in Body Composition Changes in the skeletal muscle structure and its aerobic capacity and insulin sensitivity should logically lead to changes in the body composition particularly with respect to body fat, ectopic fat and muscle mass. Important physiological mechanisms underlying exercise-stimulated improvements are reduction of overall fat mass and preservation of muscle mass that result in increased relative muscle volume. Thamer et al (2008) explored the hypothesis that the PPARD SNPs reported to have an influence on skeletal muscle function (oxidative capacity and trainability) should also influence and cause consequent changes in the body composition. They used a non invasive whole-body magnetic resonance (MR) approach including imaging and spectroscopy for precise quantification of body fat stores, muscle volume, and hepatic lipids. The study was done as a pre-post study with measurements done before and after 9 months of lifestyle interventions (LI). The whole-body magnetic resonance approach revealed that LI increases relative muscle volume with favorable effects on insulin sensitivity and hepatic lipid content. The body weight, BMI, visceral adipose tissue (VAT), and non visceral adipose tissue (NVAT) significantly decreased (P< 0.0001, all), and hepatic lipids displayed the most dramatic decline (31%, P0.0001). There were significant changes in 2-hour plasma glucose, fasting and 2-hour plasma insulin and insulin sensitivity (P Read More