High Capacity Runners Rats Research Articles

Intrinsic aerobic capacity, sex, and brain aging: Determinants of Alzheimer's disease risk.

Low aerobic capacity (or cardiorespiratory fitness) is strongly associated with all-cause mortality and risk for Alzheimer's disease (AD). Individuals with early dementia and AD have lower aerobic capacity compared to age-matched controls. The mechanism by which low aerobic capacity influences AD are unknown but are suggestive of an impairment in mitochondrial energetics. Here we used rats selectively bred over several generations to have intrinsic low or high exercise capacity. Rats were bred based on low or high capacity to complete an aerobic treadmill running test resulting in rats with robustly different intrinsic aerobic capacity despite being maintained sedentary. We examined mitochondrial function, RNA sequencing, and markers of AD in brain tissue from 18-month-old male and female Low Capacity Runners (LCR) and High Capacity Runners (HCR) from generation 43 of selection. We found lower mitochondrial respiration in brains of female LCR rats for complex I-, ADP-, uncoupled-, and complex II-driven flux when compared to LCR males. Brain Complex I driven respiratory flux was reduced in LCR females when compared to HCR females. No differences were observed in complex I or citrate synthase (CS) Vmax but complex IV Vmax was lower in LCR males versus HCR males. Female LCR rats had higher Aβ42 while both male and female LCR rats had higher phosphorylated tau at threonine 181 in whole brain homogenates. RNAseq revealed a greater effect of sex on gene expression than strain (HCR vs. LCR). However, FOXO signaling, axonal guidance, ubiquitination, and protein phosphorylation pathways were greater in male LCR versus male HCR rats. Glutamate NMDA receptor subunit 3A (Grin3a) and Transcription factor 7-like 2 (TCF7L2) were identified as coordinating numerous downstream targets with IPA analysis in male LCR rats. RNA sequencing outcomes suggest downregulation of AMPK signaling in female LCR rats. These data support a strong relationship between intrinsic aerobic capacity, sex, and markers of brain mitochondrial function and AD in late-middle aged HCR and LCR rats.

Abstract 12763: High Innate Aerobic Capacity Protects Against Angiotensin II-Induced Hypertension and Vascular Remodeling

Low aerobic capacity is associated with increased cardiovascular morbidity and mortality. A heterogeneous rat population selectively bred to segregate genes that sustain innate aerobic exercise capacity, low capacity runners (LCR) show impaired cardiac function in old age and premature death versus high capacity runners (HCR). Here we investigated whether high innate aerobic capacity offers early protection against cardiovascular disease by examining the hypertensive response of 7-month-old LCR and HCR rats to angiotensin II (Ang II, 150 μg/kg/min for 14 days). LCR and HCR rats showed no difference in basal blood pressure (105 mmHg) or vessel wall morphology, but in LCRs the mean arterial blood pressure increased to 145 mmHg versus 125 mmHg in HCRs. Congruently, LCR rats had increased aortic medial thickness and fibrosis. Aortic cytosolic and mitochondrial superoxide levels were also significantly increased in LCRs. Vascular reactivity experiments revealed impaired endothelium-dependent and -independent relaxation of mesenteric arteries of LCRs. Ang II infusion significantly increased the infiltration of macrophages into the aortic adventitia of LCRs as determined by CD68 and Mac-3 staining. Gene expression analysis by qPCR showed that markers of classically-activated macrophages CD86 and TNF-α were unchanged in rat strains but markers of alternatively-activated macrophages CD163 and Arg-1 were upregulated only in LCRs. Plasma IL-6, RANTES, CCL2 and Ang II and aortic VCAM1 levels were elevated only in LCRs whereas no difference in eNOS levels was observed between the rat strains. Aortic sections of LCRs showed increased senescence in adventitia whereas vascular smooth muscle cells (VSMC) isolated from LCR rats were more susceptible to Ang II-induced senescence. LCRs also showed increased cardiac hypertrophy and fibrosis. These data support the “outside-in” hypothesis, in which vascular inflammation initiated in adventitia progresses inwards to media and intima, causing VSMC and endothelial dysfunction, and that fibroblasts play a critical role in Ang II-induced hypertension and vascular remodeling under low innate aerobic capacity conditions, whereas high innate aerobic capacity is potentially protective against hypertension.

Rats with elevated genetic risk for metabolic syndrome exhibit cognitive deficiencies when young

Metabolic syndrome (MetS) is a known risk factor for cognitive decline. Using polygenic rat models selectively bred for high and low intrinsic exercise capacity and simultaneously modelling as low and high innate risk factor for MetS respectively, we have previously shown that adult animals with lower exercise capacity/higher MetS risk perform poorly in tasks requiring flexible cognition. However, it is not known whether these deficits in cognition are present already at young age. Also, it is unclear whether the high risk genome is related also to lower-level cognition, such as sensory gating measured as prepulse inhibition. In this study, young and adult (5-8 weeks and ~9 months) rats selectively bred for 36 generations as High-Capacity Runners (HCR) or Low-Capacity Runners (LCR) were tested for behavior in an open field task, modulation of startle reflex, and spatial learning in a T-maze. HCR rats were more active in the open field than LCR rats independent of age. Responses to the startle stimulus habituated to the same extent in LCR compared to HCR rats when young, but as adults, stronger habituation was seen in the HCR animals. The prepulse inhibition of startle response was equally strong in young HCR and LCR animals but the effect was shorter lasting in HCR animals. In T-maze, adult HCR animals unexpectedly showed attenuated learning, but we interpret this finding to stem from differences in motivation rather than learning ability. Overall, in the LCR rats with the risk genome for poor aerobic fitness and MetS, indications of compromised cognitive function are present already at a young age.

PO-201 Aging attenuates the effect of aerobic capacity in muscle and serum metabolic profile but not in white adipose tissue

Objective Aerobic capacity is a quantitative predictor of the morbidity and mortality in many diverse patient populations. While aging is the main factor affecting aerobic capacity. The present study aimed to assess the effect of aerobic capacity and aging on metabolic profile in rats and to investigate the metabolic interactions between white adipose tissue (WAT), muscle and serum.
 Methods In this study, we used rat models that were selectively bred to differ in maximal running capacity (High capacity runners (HCR) and Low capacity runners (LCR)). Part of the rats were sacrificed after 9 months and the rest at 21 months. The effect of aerobic capacity on metabolic profile was assessed from 9 months old young rats (HCR-Y and LCR-Y), while the effect of aging on the metabolic profile in different capacity rats was determined comparing 9 months to 21 months old rats (HCR-O and LCR-O). Nuclear magnetic resonance (NMR) spectroscopy was performed to detect the metabolomics of WAT, muscle and serum. Partial least-squares-discriminant analysis (PLS-DA) was used for pattern recognition between HCR-Y and LCR-Y and between HCR-O and LCR-O. Metabolites with variable influence on projection (VIP) >1.0 and p<0.05 were classified as significantly different metabolites between groups. Spearman correlation was used to assess the metabolic interactions between white adipose tissue (WAT), muscle and serum.
 Results HCR-Y rats had significantly higher skeletal muscle mass-to-body mass ratio (p<0.001), while lower body mass (p<0.001), fat mass (p<0.001), skeletal muscle mass (p=0.035) and fat mass to body mass ratio (p=0.004) than LCR-Y rats. The running capacity of HCR-Y rats was 132.7% (best running speed) better than LCR-Y rats (p<0.001). However, with age, the difference between body compositions between the two capacity groups became insignificant. HCR-O only had significantly lower body mass than the LCR-O (p=0.02). Running capacity (p=0.06) was 86.4% (best running speed) higher in the HCR-O rats than that of the LCR-O rats. PLS-DA revealed marked effects of aerobic capacity on metabolic profile in all three tissue types between HCR-Y and LCR-Y. The metabolic profile classification and prediction was best (i.e. sharper) in muscle than in WAT and serum. In addition, muscle and serum contained more significantly different metabolites than WAT in HCR-Y than in LCR-Y. Pathway analysis of the significantly different metabolites between HCR-Y and LCR-Y revealed that all the pathways belong to the lipid metabolism and amino acid metabolism in muscle while in serum it is only amino acid metabolism. However, in the case of the old groups, the PLS-DA gave reversed results. It revealed that WAT performed best in terms of classification and prediction of metabolites between HCR-O and LCR-O and had the most significantly different metabolites out of the three tissue types. The significantly different metabolites’ pathways belong to lipid metabolism in WAT. When assessing the metabolic interaction between different tissue types, all significantly different metabolites between HCR and LCR rats in young and old groups were moderately or strongly correlated (Spearman correlation between 0.45-0.9) with one or more metabolites in any of the three tissues.
 Conclusions In this study, we assessed the metabolic profile and body composition of WAT, muscle and serum in young and old rats with different aerobic capacities. We found that aerobic capacity greatly impacts body composition and the metabolic profile in muscle and serum in young rats, however the impact is attenuated with age. In addition, it is aging and not aerobic capacity that had the most influence on WAT metabolites. This suggest that WAT has more important role in aging process than previously assumed.

Deficiency in the Heat Stress Response Could Underlie Susceptibility to Metabolic Disease.

Heat treatment (HT) effectively prevents insulin resistance and glucose intolerance in rats fed a high-fat diet (HFD). The positive metabolic actions of heat shock protein 72 (HSP72), which include increased oxidative capacity and enhanced mitochondrial function, underlie the protective effects of HT. The purpose of this study was to test the ability of HSP72 induction to mitigate the effects of consumption of a short-term 3-day HFD in rats selectively bred to be low-capacity runners (LCRs) and high-capacity runners (HCRs)—selective breeding that results in disparate differences in intrinsic aerobic capacity. HCR and LCR rats were fed a chow or HFD for 3 days and received a single in vivo HT (41°C, for 20 min) or sham treatment (ST). Blood, skeletal muscles, liver, and adipose tissues were harvested 24 h after HT/ST. HT decreased blood glucose levels, adipocyte size, and triglyceride accumulation in liver and muscle and restored insulin sensitivity in glycolytic muscles from LCR rats. As expected, HCR rats were protected from the HFD. Importantly, HSP72 induction was decreased in LCR rats after only 3 days of eating the HFD. Deficiency in the highly conserved stress response mediated by HSPs could underlie susceptibility to metabolic disease with low aerobic capacity.

Effects of intrinsic aerobic capacity, aging and voluntary running on skeletal muscle sirtuins and heat shock proteins

AimSirtuins are proteins that connect energy metabolism, oxidative stress and aging. Expression of heat shock proteins (Hsps) is regulated by heat shock factors (HSFs) in response to various environmental and physiological stresses, such as oxidative stress. Oxidative stress accumulates during aging which makes cells more prone to DNA damage. Although many experimental animal models have been designed to study the effects of knockdown or overexpression of sirtuins, HSFs and Hsps, little is known about how aging per se affects their expression. Here we study the impact of intrinsic aerobic capacity, aging and voluntary exercise on the levels of sirtuins, HSFs and Hsps in skeletal muscle. MethodsWe studied the protein levels of sirtuins (SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6 and SIRT7), HSF1, HSF2, Hsp10, Hsp27 and Hsp70 before and after one-year of voluntary running intervention of rat strains selectively bred for intrinsic aerobic exercise capacity; high capacity runners (HCR) and low capacity runners (LCR) differ by more than 30% for median lifespan. This setup enabled us to discern the effects of inborn aerobic capacity, aging and exercise activity on the protein levels of sirtuins, HSFs and Hsps in skeletal muscle. ResultsOur results revealed that the longer lived HCR rats had higher SIRT3, HSF1 and HSF2 contents in skeletal muscle (gastrocnemius, p < 0.05) than LCRs. Neither aging nor voluntary running had a significant effect on the studied sirtuin proteins. Aging significantly increased the protein levels of HSF1, HSF2 and Hsp27 (p < 0.05). ConclusionOur finding of elevated SIRT3 levels in HCR rats is in line with previous studies; SIRT3 in general is linked to elevated fatty acid oxidation and oxidative phosphorylation, which previously have been associated with metabolic profile of HCRs. HSF1, HSF2 and Hsp27 levels increased with aging, showing that aged muscles responded to aging-related stress. Our study shows for the first time that SIRT3 protein level is linked to high inborn aerobic capacity, and may be directly interconnected to longevity.

High Intrinsic Aerobic Capacity Protects against Ethanol-Induced Hepatic Injury and Metabolic Dysfunction: Study Using High Capacity Runner Rat Model.

Rats artificially selected over several generations for high intrinsic endurance/aerobic capacity resulting in high capacity runners (HCR) has been developed to study the links between high aerobic fitness and protection from metabolic diseases (Wisloff et al., Science, 2005). We have previously shown that the HCR strain have elevated hepatic mitochondrial content and oxidative capacity. In this study, we tested if the elevated hepatic mitochondrial content in the HCR rat would provide “metabolic protection” from chronic ethanol-induced hepatic steatosis and injury. The Leiber-Decarli liquid diet with ethanol (7% v/v; HCR-E) and without (HCR-C) was given to HCR rats (n = 8 per group) from 14 to 20 weeks of age that were weight matched and pair-fed to assure isocaloric intake. Hepatic triglyceride (TG) content and macro- and microvesicular steatosis were significantly greater in HCR-E compared with HCR-C (p < 0.05). In addition, hepatic superoxide dismutase activity and glutathione levels were significantly (p < 0.05) reduced in the HCR-E rats. This hepatic phenotype also was associated with reduced total hepatic fatty acid oxidation (p = 0.03) and β-hydroxyacyl-CoA dehydrogenase activity (p = 0.01), and reductions in microsomal triglyceride transfer protein and apoB-100 protein content (p = 0.01) in HCR-E animals. However, despite these documented hepatic alterations, ethanol ingestion failed to induce significant hepatic liver injury, including no changes in hepatic inflammation, or serum alanine amino transferase (ALTs), free fatty acids (FFAs), triglycerides (TGs), insulin, or glucose. High intrinsic aerobic fitness did not reduce ethanol-induced hepatic steatosis, but protected against ethanol-induced hepatic injury and systemic metabolic dysfunction in a high aerobic capacity rat model.

Female rats selectively bred for high intrinsic aerobic fitness are protected from ovariectomy-associated metabolic dysfunction.

Ovariectomized rodents model human menopause in that they rapidly gain weight, reduce spontaneous physical activity (SPA), and develop metabolic dysfunction, including insulin resistance. How contrasting aerobic fitness levels impacts ovariectomy (OVX)-associated metabolic dysfunction is not known. Female rats selectively bred for high and low intrinsic aerobic fitness [high-capacity runners (HCR) and low-capacity runners (LCR), respectively] were maintained under sedentary conditions for 39 wk. Midway through the observation period, OVX or sham (SHM) operations were performed providing HCR-SHM, HCR-OVX, LCR-SHM, and LCR-OVX groups. Glucose tolerance, energy expenditure, and SPA were measured before and 4 wk after surgery, while body composition via dual-energy X-ray absorptiometry and adipose tissue distribution, brown adipose tissue (BAT), and skeletal muscle phenotype, hepatic lipid content, insulin resistance via homeostatic assessment model of insulin resistance and AdipoIR, and blood lipids were assessed at death. Remarkably, HCR were protected from OVX-associated increases in adiposity and insulin resistance, observed only in LCR. HCR rats were ∼30% smaller, had ∼70% greater spontaneous physical activity (SPA), consumed ∼10% more relative energy, had greater skeletal muscle proliferator-activated receptor coactivator 1-alpha, and ∼40% more BAT. OVX did not increase energy intake and reduced SPA to the same extent in both HCR and LCR. LCR were particularly affected by an OVX-associated reduction in resting energy expenditure and experienced a reduction in relative BAT; resting energy expenditure correlated positively with BAT across all animals (r = 0.6; P < 0.001). In conclusion, despite reduced SPA following OVX, high intrinsic aerobic fitness protects against OVX-associated increases in adiposity and insulin resistance. The mechanism may involve preservation of resting energy expenditure.

Atrial Myocyte Function and Ca2+ Handling Is Associated with Inborn Aerobic Capacity

BackgroundAlthough high aerobic capacity is associated with effective cardiac function, the effect of aerobic capacity on atrial function, especially in terms of cellular mechanisms, is not known. We aimed to investigate whether rats with low inborn maximal oxygen uptake (VO2 max) had impaired atrial myocyte contractile function when compared to rats with high inborn VO2 max.Methods and ResultsAtrial myocyte function was depressed in Low Capacity Runners (LCR) relative to High Capacity Runners (HCR) which was associated with impaired Ca2+ handling. Fractional shortening was 52% lower at 2 Hz and 60% lower at 5 Hz stimulation while time to 50% relengthening was 43% prolonged and 55% prolonged, respectively. Differences in Ca2+ amplitude and diastolic Ca2+ level were observed at 5 Hz stimulation where Ca2+ amplitude was 70% lower and diastolic Ca2+ level was 11% higher in LCR rats. Prolonged time to 50% Ca2+ decay was associated with reduced sarcoplasmic reticulum (SR) Ca2+ ATPase function in LCR (39%). Na+/Ca2+ exchanger activity was comparable between the groups. Diastolic SR Ca2+ leak was increased by 109%. This could be partly explained by increased ryanodine receptors phosphorylation at the Ca2+-calmodulin-dependent protein kinase-II specific Ser-2814 site in LCR rats. T-tubules were present in 68% of HCR cells whereas only 33% LCR cells had these structures. In HCR, the significantly higher numbers of cells with T-tubules were combined with greater numbers of myocytes where Ca2+ release in the cell occurred simultaneously in central and peripheral regions, giving rise to faster and more spatial homogenous Ca2+-signal onset.ConclusionThis data demonstrates that contrasting for low or high aerobic capacity leads to diverse functional and structural remodelling of atrial myocytes, with impaired contractile function in LCR compared to HCR rats.

Susceptibility to intracerebral hemorrhage-induced brain injury segregates with low aerobic capacity in rats

Although low exercise capacity is a risk factor for stroke, the exact mechanisms that underlie this connection are not known. As a model system for exploring the association between aerobic capacity and disease risks we applied two-way artificial selection over numerous generations in rats to produce low capacity runners (LCR) and high capacity runners (HCR). Here we compared intracerebral hemorrhage (ICH)-induced brain injury in both genders of these rat lines. HCR and LCR rats had 100μl blood injected into the right caudate and were killed at days 1, 3, 7 and 28 for brain water content determination, immunohistochemistry, histology, Western blot, and behavioral tests. Compared to male HCRs, male LCRs had more severe ICH-induced brain injury including worse brain edema, necroptosis, brain atrophy, and neurological deficits, but not increased numbers of Fluoro-Jade C positive cells or elevated cleaved caspase-3 levels. This was associated with greater microglial activation, and heme oxygenase-1 and protease activated receptor (PAR)-1 upregulation. In females, edema was also greater in LCRs than in HCRs, although it was less severe in females than in males for both LCRs and HCRs. Thus, ICH-induced brain injury was more severe in LCRs, a model of low exercise capacity, than in HCRs. Increased activation of microglia and PAR-1 may participate mechanistically in increased ICH-susceptibility. Females were protected against ICH-induced brain edema formation in both HCRs and LCRs.

Proteomic analysis reveals perturbed energy metabolism and elevated oxidative stress in hearts of rats with inborn low aerobic capacity

Selection on running capacity has created rat phenotypes of high-capacity runners (HCRs) that have enhanced cardiac function and low-capacity runners (LCRs) that exhibit risk factors of metabolic syndrome. We analysed hearts of HCRs and LCRs from generation 22 of selection using DIGE and identified proteins from MS database searches. The running capacity of HCRs was six-fold greater than LCRs. DIGE resolved 957 spots and proteins were unambiguously identified in 369 spots. Protein expression profiling detected 67 statistically significant (p<0.05; false discovery rate <10%, calculated using q-values) differences between HCRs and LCRs. Hearts of HCR rats exhibited robust increases in the abundance of each enzyme of the β-oxidation pathway. In contrast, LCR hearts were characterised by the modulation of enzymes associated with ketone body or amino acid metabolism. LCRs also exhibited enhanced expression of antioxidant enzymes such as catalase and greater phosphorylation of α B-crystallin at serine 59, which is a common point of convergence in cardiac stress signalling. Thus, proteomic analysis revealed selection on low running capacity is associated with perturbations in cardiac energy metabolism and provided the first evidence that the LCR cardiac proteome is exposed to greater oxidative stress.

Lower oxidative DNA damage despite greater ROS production in muscles from rats selectively bred for high running capacity

Artificial selection in rat has yielded high-capacity runners (HCR) and low-capacity runners (LCR) that differ in intrinsic (untrained) aerobic exercise ability and metabolic disease risk. To gain insight into how oxygen metabolism may have been affected by selection, we compared mitochondrial function, oxidative DNA damage (8-dihydroxy-guanosine; 8dOHG), and antioxidant enzyme activities in soleus muscle (Sol) and gastrocnemius muscle (Gas) of adult and aged LCR vs. HCR rats. In Sol of adult HCR rats, maximal ADP-stimulated respiration was 37% greater, whereas in Gas of adult HCR rats, there was a 23% greater complex IV-driven respiratory capacity and 54% greater leak as a fraction of electron transport capacity (suggesting looser mitochondrial coupling) vs. LCR rats. H(2)O(2) emission per gram of muscle was 24-26% greater for both muscles in adult HCR rats vs. LCR, although H(2)O(2) emission in Gas was 17% lower in HCR, after normalizing for citrate synthase activity (marker of mitochondrial content). Despite greater H(2)O(2) emission, 8dOHG levels were 62-78% lower in HCR rats due to 62-96% higher superoxide dismutase activity in both muscles and 47% higher catalase activity in Sol muscle in adult HCR rats, with no evidence for higher 8 oxoguanine glycosylase (OGG1; DNA repair enzyme) protein expression. We conclude that genetic segregation for high running capacity has generated a molecular network of cellular adaptations, facilitating a superior response to oxidative stress.

Skeletal muscle mitochondrial and metabolic responses to a high-fat diet in female rats bred for high and low aerobic capacity

Rats selected artificially to be low-capacity runners (LCR) possess a metabolic syndrome phenotype that is worsened by a high-fat diet (HFD), whereas rats selected to be high-capacity runners (HCR) are protected against HFD-induced obesity and insulin resistance. This study examined whether protection against, or susceptibility to, HFD-induced insulin resistance in the HCR-LCR strains is associated with contrasting metabolic adaptations in skeletal muscle. HCR and LCR rats (generation 20; n = 5-6; maximum running distance approximately 1800 m vs. approximately 350 m, respectively (p < 0.0001)) were divided into HFD (71.6% energy from fat) or normal chow (NC) (16.7% energy from fat) groups for 7 weeks (from 24 to 31 weeks of age). Skeletal muscle (red gastrocnemius) mitochondrial-fatty acid oxidation (FAO), mitochondrial-enzyme activity, mitochondrial-morphology, peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha), and peroxisome proliferator-activated receptor delta (PPARdelta) expression and insulin sensitivity (intraperitoneal glucose tolerance tests) were measured. The HFD caused increased adiposity and reduced insulin sensitivity only in the LCR and not the HCR strain. Isolated mitochondria from the HCR skeletal muscle displayed a 2-fold-higher rate of FAO on NC, but both groups increased FAO following HFD. PGC-1alpha mRNA expression and superoxide dismutase activity were significantly reduced with the HFD in the LCR rats, but not in the HCR rats. PPARdelta expression did not differ between strains or dietary conditions. These results do not provide a clear connection between protection of insulin sensitivity and HFD-induced adaptive changes in mitochondrial function or transcriptional responses but do not dismiss the possibility that elevated mitochondrial FAO in the HCR may play a protective role.

Initial signaling response to acute exercise bout is similar in hearts of rats bred for divergent exercise capacities

Rats artificially selected as low capacity runners (LCR) exhibit features of the metabolic syndrome, and blunted exercise training-induced cardiac hypertrophy compared with high capacity runners (HCR). We tested the hypothesis that the divergent cardiac phenotypes may be due to diminished activation of signaling proteins in LCR vs HCR rats. LCR (n=18) and HCR (n=18) rats were randomly assigned to acute exercise or control groups. Ten minutes after a 10-min bout of high intensity treadmill exercise, rats were euthanized, and left ventricles (LV) were harvested. LV homogenates were immunoblotted for phosphorylated and total levels of extracellular regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK), p38, Akt, S6, and the ribosomal S6 protein kinases S6K and p90RSK. Alterations in protein ubiquitination were examined as an index of protein turnover. In LCR and HCR rats, S6 was activated to a similar extent after exercise (5-fold vs control), as were JNK1/2, p38, and ERK1/2 (each 1.5-fold). Exercise significantly reduced ubiquitination of some proteins, suggesting diminished post-exercise protein degradation. That no significant LCR/HCR differences were observed 10-min post-exercise in the signaling pathways studied herein suggests that the source of the differing cardiac phenotypes in LCR/HCR rats may involve differing activation times and/or other signaling pathways.

Dysregulation of muscle lipid metabolism in rats selectively bred for low aerobic running capacity

As substrate for evaluation of metabolic diseases, we developed novel rat models that contrast for endurance exercise capacity. Through two-way artificial selection, we created rodent phenotypes of intrinsically low-capacity runners (LCR) and high-capacity runners (HCR) that also differed markedly for cardiovascular and metabolic disease risk factors. Here, we determined skeletal muscle proteins with putative roles in lipid and carbohydrate metabolism to better understand the mechanisms underlying differences in whole body substrate handling between phenotypes. Animals (generation 16) differed for endurance running capacity by 295%. LCR animals had higher resting plasma glucose (6.58 +/- 0.45 vs. 6.09 +/- 0.45 mmol/l), insulin (0.48 +/- 0.03 vs. 0.32 +/- 0.02 ng/ml), nonesterified fatty acid (0.57 +/- 0.14 v 0.35 +/- 0.05 mM), and triglyceride (TG; 0.47 +/- 0.11 vs. 0.25 +/- 0.08 mmol/l) concentrations (all P < 0.05). Muscle TG (72.3 +/- 14.7 vs. 38.9 +/- 6.2 mmol/kg dry muscle wt; P < 0.05) and diacylglycerol (96 +/- 28 vs. 42 +/- 8 pmol/mg dry muscle wt; P < 0.05) contents were elevated in LCR vs. HCR rats. Accompanying the greater lipid accretion in LCR was increased fatty acid translocase/CD36 content (1,014 +/- 80 vs. 781 +/- 70 arbitrary units; P < 0.05) and reduced TG lipase activity (0.158 +/- 0.0125 vs. 0.274 +/- 0.018 mmol.min(-1).kg dry muscle wt(-1); P < 0.05). Muscle glycogen, GLUT4 protein, and basal phosphorylation states of AMP-activated protein kinase-alpha1, AMP-activated protein kinase-alpha2, and acetyl-CoA carboxylase were similar in LCR and HCR. In conclusion, rats with low intrinsic aerobic capacity demonstrate abnormalities in lipid-handling capacity. These disruptions may, in part, be responsible for the increased risk of metabolic disorders observed in this phenotype.

It's all in the genes, so pick your parents wisely

Aerobic exercise capacity is a complex phenotype influenced by a myriad of environmental and genetic factors. At one end of the continuum, elite endurance athletes represent a rare union of genetic potential that, given appropriate environmental stimulus (e.g., training, nutrition) can culminate in