Lauren G Koch

University of Michigan, Ann Arbor, Michigan, United States

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Publications (119)406.87 Total impact

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    ABSTRACT: Prolonged mechanical ventilation (MV) leads to rapid diaphragmatic atrophy and contractile dysfunction, which is collectively termed "ventilator-induced diaphragm dysfunction" (VIDD). Interestingly, endurance-exercise training prior to MV has been shown to protect against VIDD. Further, recent evidence reveals that sedentary animals selectively bred to possess a high aerobic capacity possess a similar skeletal muscle phenotype to muscles from endurance trained animals. Therefore, we tested the hypothesis that animals with a high intrinsic aerobic capacity would naturally be afforded protection against VIDD. To this end, animals were selectively bred over 33 generations to create two divergent strains, differing in aerobic capacity; high capacity runners (HCR) and low capacity runners (LCR). Both groups of animals were subjected to 12 hours of MV and compared to non-ventilated control animals within the same strains. As expected, contrasted to LCR animals, the diaphragm muscle from the HCR animals contained higher levels of oxidative enzymes (e.g., citrate synthase) and antioxidant enzymes (e.g., superoxide dismutase and catalase). Nonetheless, compared to non-ventilated controls, prolonged MV resulted in significant diaphragmatic atrophy and impaired diaphragm contractile function in both the HCR and LCR animals and the magnitude of VIDD did not differ between strains. In conclusion, these data demonstrate that possession of a high intrinsic aerobic capacity alone does not afford protection against VIDD. Importantly, these results suggest that endurance-exercise training differentially alters the diaphragm phenotype to resist VIDD. Interestingly, levels of heat shock protein 72 did not differ between strains; thus, potentially representing an important area of difference between animals. Copyright © 2014, Journal of Applied Physiology.
    Journal of applied physiology (Bethesda, Md. : 1985). 01/2015;
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    ABSTRACT: The oxidative stress effect of exercise training on testis function is under debate. In the present study we used a unique rat model system developed by artificial selection for low and high intrinsic running capacity (LCR and HCR, respectively) to evaluate the effects of exercise training on apoptosis and spermatogenesis in testis. Twenty-four 13-month-old male rats were assigned to four groups: control LCR (LCR-C), trained LCR (LCR-T), control HCR (HCR-C), and trained HCR (HCR-T). Ten key proteins connecting aerobic exercise capacity and general testes function were assessed, including those that are vital for mitochondrial biogenesis. The VO2 max of LCR-C group was about 30% lower than that of HCR-C rats, and the SIRT1 levels were also significantly lower than HCR-C. Twelve weeks of training significantly increased maximal oxygen consumption in LCR by nearly 40% whereas HCR remained unchanged. LCR-T had significantly higher levels of peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1α), decreased levels of reactive oxygen species and increased acetylated p53 compared to LCR-C, while training produced no significant changes for these measures in HCR rats. BAX and Blc-2 were not different among all four groups. The levels of outer dense fibers -1 (Odf-1), a marker of spermatogenesis, increased in LCR-T rats, but decreased in HCR-TR rats. Moreover, exercise training increased the levels of lactate dehydrogenase C (LDHC) only in LCR rats. These data suggest that rats with low inborn exercise capacity can increase whole body oxygen consumption and running exercise capacity with endurance training and, in turn, increase spermatogenesis function via reduction in ROS and heightened activity of p53 in testes.
    PLoS ONE 12/2014; 9(12):e114075. · 3.53 Impact Factor
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    ABSTRACT: Daily physical activity shows substantial inter-individual variation, and low physical activity is associated with obesity and weight gain. Elevated physical activity is also associated with high intrinsic aerobic capacity, which confers considerable metabolic health benefits. Rats artificially selected for high intrinsic aerobic capacity (high-capacity runners, HCR) are more physically active than their low-capacity counterparts (low-capacity runners, LCR). To test the hypothesis that physical activity counters metabolic thriftiness, we measured physical activity and weight loss during three weeks of 50% calorie restriction (CR) in the HCR and LCR rat lines. At baseline, HCR ate more and were more active than LCR; this was seen in male rats, where LCR are considerably heavier than HCR, as well as in a set of female rats where body weight did not differ between the lines, demonstrating that this effect is consistent across sex and not secondary to body weight. We show for the first time that HCR lose more weight than LCR relative to baseline. Physical activity levels declined throughout CR, and this was more pronounced in HCR than in LCR, yet some aspects of activity remained elevated in HCR relative to LCR even during CR. This is consistent with the idea that low physical activity contributes to metabolic thriftiness during food restriction, allowing LCR to defend body mass, particularly lean mass. This has implications for physical activity during diet-induced weight loss, the genetic underpinnings of individual differences in weight loss during a diet, and the potential evolutionary opposition between metabolic thriftiness and aerobic capacity. Copyright © 2014 Elsevier Inc. All rights reserved.
    Physiology & Behavior 11/2014; 139C:303-313. · 3.03 Impact Factor
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    ABSTRACT: Exercise capacity and dietary restriction (DR) are linked to improved quality of life, including enhanced brain function and neuro-protection. Brain derived neurotrophic factor (BDNF) is one of the key proteins involved in the beneficial effects of exercise on brain. Low capacity runner (LCR) and high capacity runner (HCR) rats were subjected to DR in order to investigate the regulation of BDNF. HCR-DR rats out-performed other groups in a passive avoidance test. BDNF content increased significantly in the hippocampus of HCR-DR groups compared to control groups (p < 0.05). The acetylation of H3 increased significantly only in the LCR-DR group. However, Chip-assay revealed that the specific binding between acetylated histone H3 and BNDF promoter was increased in both LCR-DR and HCR-DR groups. In spite of these increases in binding, at the transcriptional level only, the LCR-DR group showed an increase in BDNF mRNA content. Additionally, DR also induced the activity of cAMP response element-binding protein (CREB), while the content of SIRT1 was not altered. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) was elevated in HCR-DR groups. But, based on the levels of nuclear respiratory factor-1 and cytocrome c oxidase, it appears that DR did not cause mitochondrial biogenesis. The data suggest that DR-mediated induction of BDNF levels includes chromatin remodeling. Moreover, DR does not induce mitochondrial biogenesis in the hippocampus of LCR/HCR rats. DR results in different responses to a passive avoidance test, and BDNF regulation in LCR and HCR rats.
    Brain Research Bulletin 08/2014; · 2.97 Impact Factor
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    ABSTRACT: Objectives Diabetes leads to cognitive impairment and is associated with age-related neurodegenerative diseases including Alzheimer's disease (AD). Thus, understanding diabetes-induced alterations in brain function is important for developing early interventions for neurodegeneration. Low-capacity runner (LCR) rats are obese and manifest metabolic risk factors resembling human “impaired glucose tolerance” or metabolic syndrome. We examined hippocampal function in aged LCR rats compared to their high-capacity runner (HCR) rat counterparts.Methods Hippocampal function was examined using proton magnetic resonance spectroscopy and imaging, unbiased stereology analysis, and a Y maze. Changes in the mitochondrial respiratory chain function and levels of hyperphosphorylated tau and mitochondrial transcriptional regulators were examined.ResultsThe levels of glutamate, myo-inositol, taurine, and choline-containing compounds were significantly increased in the aged LCR rats. We observed a significant loss of hippocampal neurons and impaired cognitive function in aged LCR rats. Respiratory chain function and activity were significantly decreased in the aged LCR rats. Hyperphosphorylated tau was accumulated within mitochondria and peroxisome proliferator-activated receptor-gamma coactivator 1α, the NAD+-dependent protein deacetylase sirtuin 1, and mitochondrial transcription factor A were downregulated in the aged LCR rat hippocampus.InterpretationThese data provide evidence of a neurodegenerative process in the hippocampus of aged LCR rats, consistent with those seen in aged-related dementing illnesses such as AD in humans. The metabolic and mitochondrial abnormalities observed in LCR rat hippocampus are similar to well-described mechanisms that lead to diabetic neuropathy and may provide an important link between cognitive and metabolic dysfunction.
    Annals of Clinical and Translational Neurology. 07/2014;
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    ABSTRACT: We report automated and time efficient (2 h per sample) profiling of muscle using ultra-performance liquid chromatography (LC) coupled directly with high-definition mass spectrometry (HDMSE). Soluble proteins extracted from rat gastrocnemius (n = 10) were digested with trypsin and analysed in duplicate using a 90 min RPLC gradient. Protein identification and label-free quantitation were performed from HDMSE spectra analysed using TransOmics Informatics for Proteomics software. In total 1,514 proteins were identified. Of these, 811 had at least 3 unique peptides and were subsequently used to assess the dynamic range and precision of LC-HDMSE label-free profiling. Proteins analysed by LC-HDMSE encompass the entire complement of glycolytic, beta-oxidation and tricarboxylic acid enzymes. In addition, numerous components of the electron transport chain and protein kinases involved in skeletal muscle regulation were detected. The dynamic range of protein abundances spanned 4 orders of magnitude. The correlation between technical replicates of the 10 biological samples was R2 = 0.9961 ± 0.0036 (95% CI = 0.9940 – 0.9992) and the technical coefficient of variation averaged 7.3 ± 6.7% (95% CI = 6.87 – 7.79%). This represents the most sophisticated label-free profiling of skeletal muscle to date.This article is protected by copyright. All rights reserved
    Proteomics 07/2014; · 3.97 Impact Factor
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    ABSTRACT: Rats selectively bred for high- and low-capacity for running on a treadmill (HCR; LCR) also differ in wheel-running behavior, but whether wheel-running can be explained by intrinsic or adaptive brain mechanisms is not as yet understood. It is established that motivation of locomotory behavior is driven by dopaminergic transmission in mesolimbic and mesostriatal systems. However, whether voluntary wheel running is associated with enkephalinergic activity in the ventral striatum is not known. Materials & Methods 40 male (20 HCR and 20 LCR) and 40 female (20 HCR and 20 LCR) rats were randomly assigned to 3 weeks of activity wheel exposure or sedentary conditions without wheel access. After 3 weeks of activity-wheel running, rats were decapitated and brains were extracted. Coronal sections were analyzed utilizing in situ hybridization histochemistry for enkephalin (ENK) mRNA in the ventral striatum. Results HCR rats expressed less ENK than LCR rats in the nucleus accumbens among females (p<.01) and in the olfactory tubercle among both females (p<.05) and males (p<.05). There was no effect of wheel running on ENK mRNA expression. Conclusion Line differences in ENK expression in the olfactory tubercle, and possibly the nucleus accumbens, partly explain divergent wheel-running behavior. The lower striatal ENK in the HCR line is consistent with enhanced dopaminergic tone, which may explain the increased motivation for wheel running observed in the HCR line.
    Brain Research 07/2014; · 2.83 Impact Factor
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    ABSTRACT: Aerobic capacity/fitness significantly impacts susceptibility for fatty liver and diabetes, but the mechanisms remain unknown. Herein we utilized rats selectively bred for high (HCR) and low (LCR) intrinsic aerobic capacity to examine the mechanisms by which aerobic capacity impacts metabolic vulnerability for fatty liver following a 3-day high fat diet (HFD). Indirect calorimetry assessment of energy metabolism combined with radiolabeled dietary food was employed to examine systemic metabolism in combination with ex vivo measures of hepatic lipid oxidation. The LCR, but not HCR, displayed increased hepatic lipid accumulation in response to the HFD despite both groups increasing energy intake. However, LCR rats had a greater increase in energy intake and demonstrated greater daily weight gain and percent body fat due to HFD compared to HCR. Additionally, total energy expenditure was higher in the larger LCR. However, controlling for the difference in body weight, the LCR has lower resting energy expenditure compared to HCR. Importantly, respiratory quotient was significantly higher during the HFD in the LCR compared to HCR, suggesting reduced whole-body lipid utilization in the LCR. This was confirmed by the observed lower whole-body dietary fatty acid oxidation in LCR compared to HCR. Further, LCR liver homogenate and isolated mitochondria showed lower complete fatty acid oxidation compared to HCR. Conclusion: Rats bred for low intrinsic aerobic capacity show greater susceptibility for dietary-induced hepatic steatosis, which is associated with a lower energy expenditure and reduced whole-body and hepatic mitochondrial lipid oxidation.
    American journal of physiology. Endocrinology and metabolism. 06/2014;
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    ABSTRACT: Trainability is important in elite sport and in recreational physical activity, and the wide range for response to training is largely dependent on genotype. In this study, we compare a newly developed rat model system selectively bred for low and high gain in running distance from aerobic training to test whether genetic segregation for trainability associates with differences in factors associated with mitochondrial biogenesis. Low response trainer (LRT) and high response trainer (HRT) rats from generation 11 of artificial selection were trained five times a week, 30 min per day for 3 months at 70 % VO2max to study the mitochondrial molecular background of trainability. As expected, we found significant differential for the gain in running distance between LRT and HRT groups as a result of training. However, the changes in VO2max, COX-4, redox homeostasis associated markers (reactive oxygen species (ROS)), silent mating-type information regulation 2 homolog (SIRT1), NAD(+)/NADH ratio, proteasome (R2 subunit), and mitochondrial network related proteins such as mitochondrial fission protein 1 (Fis1) and mitochondrial fusion protein (Mfn1) suggest that these markers are not strongly involved in the differences in trainability between LRT and HRT. On the other hand, according to our results, we discovered that differences in basal activity of AMP-activated protein kinase alpha (AMPKα) and differential changes in aerobic exercise-induced responses of citrate synthase, carbonylated protein, peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1-α), nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (TFAM), and Lon protease limit trainability between these selected lines. From this, we conclude that mitochondrial biogenesis-associated factors adapt differently to aerobic exercise training in training sensitive and training resistant rats.
    Pflugers Archiv : European journal of physiology. 06/2014;
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    ABSTRACT: Differences in intrinsic aerobic capacity play a critical role in the development of perturbed metabolism, chronic disease and all-cause mortality. Aims were to employ metabolomics to examine differences in age vs. aerobic capacity in young and old rats selectively bred for low (LCR) or high (HCR) aerobic capacity. Proton nuclear magnetic resonance spectroscopy (1H-NMR) evaluated the metabolic profile of plasma samples obtained from fasted LCR and HCR. Multivariate statistical analysis was employed, with individual features judged based on variability R2 and predictive ability Q2 in unsupervised and supervised models built using the most significant metabolites. Taurine, pyruvate, acetone, valine, amongst others were key metabolites that contributed to distinct separation based on age (R2=0.83, Q2=0.65). In contrast, weaker predictive models were observed for LCR vs. HCR with scores of R2=0.53 and Q2=0.35 respectively. Key metabolites that decreased in HCR compared to LCR included isopropanol, o-acetylcarnithine, sarcosine and proline. Pathway analysis highlighted changes in methionine, purine and TCA cycle intermediates. In conclusion, metabolomics analysis was a better predictor and age rather than aerobic capacity in LCR and HCR rats. This observation highlights the importance of age when attempting to isolate metabolic changes in aerobic capacity and their relation to chronic disease risk.
    Experimental Biology 2014 **Exercise Health and Disease**, San Diego; 04/2014
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    ABSTRACT: Profiling of protein species is important because gene polymorphisms, splice variations and post-translational modifications may combine and give rise to multiple protein species that have different effects on cellular function. Two-dimensional gel electrophoresis is one of the most robust methods for differential analysis of protein species, but bioinformatic interrogation is challenging because the consequences of changes in the abundance of individual protein species on cell function are unknown and cannot be predicted. We conducted DIGE of soleus muscle from male and female rats artificially selected as either high- or low-capacity runners (HCR and LCR, respectively). In total 696 protein species were resolved and LC-MS/MS identified proteins in 337 spots. Forty protein species were differentially (P<0.05, FDR<10 %) expressed between HCR and LCR and conditional independence mapping found distinct networks within these data, which brought insight beyond that achieved by functional annotation. Protein disulfide isomerase A3 emerged as a key node segregating with differences in aerobic capacity and unsupervised bibliometric analysis highlighted further links to signal transducer and activator of transcription 3, which were confirmed by western blotting. Thus, conditional independence mapping is a useful technique for interrogating DIGE data that is capable of highlighting latent features. Quantitative proteome profiling revealed there is little or no sexual dimorphism in the skeletal muscle response to artificial selection on running capacity. Instead we found noncanonical STAT3 signalling may be associated with low exercise capacity and skeletal muscle insulin resistance. Importantly, this discovery was made using unsupervised multivariate association mapping and bibliometric network analyses. This allowed our interpretation of the findings to be guided by patterns within the data rather than our preconceptions about which proteins or processes are of greatest interest. Moreover, we demonstrate this novel approach can be applied to 2D gel analysis, which is unsurpassed in its ability to profile protein species but currently has few dedicated bioinformatic tools.
    Journal of proteomics 04/2014; · 5.07 Impact Factor
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    ABSTRACT: A high-calorie diet accompanied by low levels of physical activity (PA) accounts for the widespread prevalence of obesity today. Yet, some people remain lean even in this obesogenic environment. Here, we investigate the cause for this exception. A key trait that predicts high PA in both humans and laboratory rodents is intrinsic aerobic capacity. Rats artificially selected as high capacity runners (HCR) are lean and consistently more physically active than their low- capacity runner (LCR) counterparts; this applies to both males and females. Here, we demonstrate that HCR show heightened total energy expenditure (TEE) and hypothesize that this is due to higher non-resting energy expenditure (NREE). After matching for body weight and lean mass, female HCR consistently had heightened non-resting EE, but not resting EE, compared to female LCR. Because of the dominant role of skeletal muscle in non-resting EE, we examined muscle energy use. We found that lean female HCR had higher muscle heat dissipation during activity, explaining their low economy of activity and high activity EE. This may be due to the amplified skeletal muscle expression levels of proteins involved in EE, and reduced expression levels of proteins involved in energy conservation, in HCR relative to LCR. This is also associated with an increased sympathetic drive to skeletal muscle in HCR compared to LCR. We find little support for the hypothesis that resting metabolic rate is correlated with maximal aerobic capacity if body size and composition are fully considered; rather, the critical factor appears to be activity thermogenesis.
    AJP Endocrinology and Metabolism 01/2014; · 4.51 Impact Factor
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    ABSTRACT: Low capacity runner (LCR) rats have been developed by divergent artificial selection for treadmill endurance capacity to explore an aerobic biology-disease connection. The beneficial effects of resveratrol supplementation have been demonstrated in endurance running. In this study it was examined whether 12 weeks of treadmill exercise training and/or resveratrol can retrieve the low running performance of the LCR and impact mitochondrial biogenesis and quality control. Resveratrol regressed running performance in trained LCR (p<0.05). Surprisingly, exercise and resveratrol treatments significantly decreased pAMPK/AMPK, SIRT1, SIRT4, forkhead transcription factor 1 (FOXO1) and mitochondrial transcription factor A (TFAM) levels in these animals (p<0.05). Mitochondrial fusion protein, HSP78 and polynucleotide phosphorylase were significantly induced in LCR-trained, LCR-resveratrol treated, LCR-trained and resveratol treated groups compared to LCR-controls. The data indicate that the AMPK-SIRT1-NAMPT-FOXO1 axis could be important to the limited aerobic endurance capacity of low running capacity rats. Resveratrol supplementation was not beneficial in terms of aerobic endurance performance, mitochondrial biogenesis, or quality control.
    Dose-Response 01/2014; 12(1):57-71. · 1.23 Impact Factor
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    ABSTRACT: Obesity alters the therapeutic window of sedative/hypnotic drugs and increases the probability of respiratory complications. The current experiments used an established rodent model of obesity to test the hypothesis that the sedative/hypnotic drugs eszopiclone and dexmedetomidine alter ventilation differentially in obese rats compared with lean/fit rats. This study used a within-groups/between-groups experimental design. University of Michigan. Experiments were conducted using lean/fit rats (n = 21) and obese rats (n = 21) that have features of metabolic syndrome. Breathing was measured with whole-body plethysmography after systemic administration of vehicle (control), the nonbenzodiazepine, benzodiazepine site agonist eszopiclone, or the alpha-2 adrenergic receptor agonist dexmedetomidine. Data were analyzed using two-way analysis of variance and appropriate post hoc comparisons. At baseline, the obese/metabolic syndrome rats had increased respiratory rates (21.6%), lower tidal volumes/body weight (-24.1%), and no differences in minute ventilation compared to lean/fit rats. In the obese rats, respiratory rate was decreased by dexmedetomidine (-29%), but not eszopiclone. In the lean and the obese rats, eszopiclone decreased tidal volume (-12%). Both sedative/hypnotic drugs caused a greater decrease in minute ventilation in the obese (-26.3%) than lean (-18%) rats. Inspiratory flow rate (VT / TI) of the obese rats was decreased by dexmedetomidine (-10.6%) and eszopiclone (-18%). Duty cycle (TI / TTOT) in both rat lines was decreased by dexmedetomidine (-16.5%) but not by eszopiclone. Dexmedetomidine, in contrast to eszopiclone, decreased minute ventilation in the obese/metabolic syndrome rats by depressing both duty cycle and inspiratory flow rate. The results show for the first time that the obese phenotype differentially modulates the respiratory effects of eszopiclone and dexmedetomidine. These differences in breathing are consistent with previously documented differences in sleep between lean/fit and obese rats. These findings also encourage future studies of obese/metabolic syndrome rats that quantify the effect of sedative/hypnotic drugs on respiratory mechanics as well as hypoxic and hypercapnic ventilatory responses. Continued findings of favorable homology between obese humans and rodents will support the interpretation that these obese rats offer a unique animal model for mechanistic studies. Filbey WA, Sanford DT, Baghdoyan HA, Koch LG, Britton SL, Lydic R. Eszopiclone and dexmedetomidine depress ventilation in obese rats with features of metabolic syndrome. SLEEP 2014;37(5):871-880.
    Sleep 01/2014; 37(5):871-880. · 5.06 Impact Factor
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    ABSTRACT: Two-dimensional gel electrophoresis provides robust comparative analysis of skeletal muscle, but this technique is laborious and limited by its inability to resolve all proteins. In contrast, orthogonal separation by SDS-PAGE and reverse-phase liquid chromatography (RPLC) coupled to mass spectrometry (MS) affords deep mining of the muscle proteome, but differential analysis between samples is challenging due to the greater level of fractionation and the complexities of quantifying proteins based on the abundances of their tryptic peptides. Here we report simple, semi-automated and time efficient (i.e., 3 h per sample) proteome profiling of skeletal muscle by 1-dimensional RPLC electrospray ionisation tandem MS. Solei were analysed from rats (n = 5, in each group) bred as either high- or low-capacity runners (HCR and LCR, respectively) that exhibited a 6.4-fold difference (1,625 ± 112 m vs. 252 ± 43 m, p < 0.0001) in running capacity during a standardized treadmill test. Soluble muscle proteins were extracted, digested with trypsin and individual biological replicates (50 ng of tryptic peptides) subjected to LC-MS profiling. Proteins were identified by triplicate LC-MS/MS analysis of a pooled sample of each biological replicate. Differential expression profiling was performed on relative abundances (RA) of parent ions, which spanned three orders of magnitude. In total, 207 proteins were analysed, which encompassed almost all enzymes of the major metabolic pathways in skeletal muscle. The most abundant protein detected was type I myosin heavy chain (RA = 5,843 ± 897) and the least abundant protein detected was heat shock 70 kDa protein (RA = 2 ± 0.5). Sixteen proteins were significantly (p < 0.05) more abundant in HCR muscle and hierarchal clustering of the profiling data highlighted two protein subgroups, which encompassed proteins associated with either the respiratory chain or fatty acid oxidation. Heart-type fatty acid binding protein (FABPH) was 1.54-fold (p = 0.0064) more abundant in HCR than LCR soleus. This discovery was verified using selective reaction monitoring (SRM) of the y5 ion (551.21 m/z) of the doubly-charged peptide SLGVGFATR (454.19 m/z) of residues 23-31 of FABPH. SRM was conducted on technical replicates of each biological sample and exhibited a coefficient of variation of 20%. The abundance of FABPH measured by SRM was 2.84-fold greater (p = 0.0095) in HCR muscle. In addition, SRM of FABPH was performed in vastus lateralis samples of young and elderly humans with different habitual activity levels (collected during a previous study) finding FABPH abundance was 2.23-fold greater (p = 0.0396) in endurance-trained individuals regardless of differences in age. In summary, our findings in HCR/LCR rats provide protein-level confirmation for earlier transcriptome profiling work and show LC-MS is a viable means of profiling the abundance of almost all major metabolic enzymes of skeletal muscle in a highly parallel manner. Moreover, our approach is relatively more time efficient than techniques relying on orthogonal separations, and we demonstrate LC-MS profiling of the HCR/LCR selection model was able to highlight biomarkers that also exhibit differences in trained and untrained human muscle.
    Proteomes. 12/2013; 1(3):290-308.
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    ABSTRACT: Background: Maximal oxygen uptake (VO2max) is a strong prognostic marker for morbidity and mortality but the cardio protective effect of high inborn VO2max remains unresolved. We aimed to investigate whether rats with high inborn VO2max yield cardio protection after myocardial infarction (MI) compared to rats with low inborn VO2max. Methods and Results: Rats breed for High Capacity of Running (HCR) or Low Capacity of Running (LCR) were randomized into; HCR-SH (sham), HCR-MI, LCR-SH and LCR-MI. VO2max was lower in HCR-MI and LCR-MI compared to respective sham (P<0.01), supported by a loss in global cardiac function, assessed by echocardiography. Fura-2/AM loaded cardiomyocyte experiments revealed that HCR-MI and LCR-MI decreased cardiomyocyte shortening (39%, and 34% reduction, respectively, both P<0.01), lowered Ca(2+) transient amplitude (37%, P<0.01, and 20% reduction, respectively) and reduced sarcoplasmic reticulum (SR) Ca(2+) content (both; 20%, P<0.01) compared to respective sham. Diastolic Ca(2+) cycling was impaired in HCR-MI and LCR-MI evidenced by prolonged time to 50% Ca(2+)-decay that was partly explained by the 47% (P<0.01) and 44% (P<0.05) decrease in SR Ca(2+) ATPase Ca(2+) removal, respectively. SR Ca(2+) leak increased by 177% in HCR-MI (P<0.01) and 67% in LCR-MI (P<0.01), which was abolished by inhibition of Ca(2+)/calmodulin-dependent protein kinase II. Conclusions: This study demonstrates that the effect MI in HCR rats was similar or even more pronounced on cardiac- and cardiomyocyte contractile function as well as on Ca(2+) handling properties compared to observations in LCR. Thus, our data do not support a cardio protective effect of higher inborn aerobic capacity.
    Journal of Applied Physiology 10/2013; · 3.43 Impact Factor
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    ABSTRACT: Aerobic capacity is a strong predictor of all-cause mortality and can influence many complex traits. To explore the biological basis underlying this connection, we developed via artificial selection two rat lines that diverge for intrinsic (i.e. inborn) aerobic capacity and differ in risk for complex disease traits. Here we conduct the first in-depth pedigree and molecular genetic analysis of these lines, the high capacity runners (HCR) and low capacity runners (LCR). Our results show that both HCR and LCR lines maintain considerable narrow-sense heritability (h(2)) for the running capacity phenotype over 28 generations (h(2) = 0.47 ± 0.02 and 0.43 ± 0.02, respectively). To minimize inbreeding, the lines were maintained by rotational mating. Pedigree records predict that the inbreeding coefficient increases at a rate of <1% per generation, ~37-38% slower than expected for random mating. Genome-wide 10K SNP genotype data for generations 5, 14, and 26 demonstrate substantial genomic evolution: between-line differentiation increased progressively, while within-line diversity deceased. Genome-wide average heterozygosity decreased at a rate of <1% per generation, consistent with pedigree-based predictions and confirming the effectiveness of rotational breeding. Linkage disequilibrium index r(2) decreases to 0.3 at ~3 Mb, suggesting that the resolution for mapping quantitative trait loci (QTL) can be as high as 2-3 cM. To establish a test population for QTL mapping, we conducted an HCR-LCR intercross. Running capacity of the F1 population (n=176) was intermediate of the HCR and LCR parentals (28 pairs); and the F2 population (n=645) showed a wider range of phenotypic distribution. Importantly, heritability in the F0-F2 pedigree remained high (h(2)~0.6). These results suggest that the HCR-LCR lines can serve as a valuable system for studying genomic evolution, and a powerful resource for mapping QTL for a host of characters relevant to human health.
    PLoS ONE 10/2013; 8(10):e77588. · 3.53 Impact Factor

Publication Stats

1k Citations
406.87 Total Impact Points

Institutions

  • 2005–2014
    • University of Michigan
      • • Department of Internal Medicine
      • • Department of Anesthesiology
      • • Department of Physical Medicine and Rehabilitation
      Ann Arbor, Michigan, United States
    • Baylor College of Medicine
      • Department of Physical Medicine & Rehabilitation
      Houston, TX, United States
  • 2013
    • Semmelweis University
      • Research Institute of Sport Sciences
      Budapest, Budapest fovaros, Hungary
    • University of Texas Medical Branch at Galveston
      Galveston, Texas, United States
  • 2012
    • University of Colorado
      Denver, Colorado, United States
    • Kent State University
      • Department of Biological Sciences
      Kent, OH, United States
  • 2010–2012
    • University of Jyväskylä
      • • Department of Psychology
      • • Department of Biology of Physical Activity
      Jyväskylä, Western Finland, Finland
    • Melbourne Institute of Technology
      Melbourne, Victoria, Australia
    • University of Missouri
      • Department of Biomedical Sciences
      Columbia, MO, United States
  • 2011
    • Liverpool John Moores University
      • Research Institute for Sport and Exercise Sciences (RISES)
      Liverpool, ENG, United Kingdom
    • RMIT University
      • School of Medical Sciences
      Melbourne, Victoria, Australia
    • University of Glasgow
      • Institute of Cardiovascular and Medical Sciences
      Glasgow, SCT, United Kingdom
  • 2009
    • Joslin Diabetes Center
      Boston, Massachusetts, United States
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
  • 2005–2009
    • Norwegian University of Science and Technology
      • Department of Circulation and Medical Imaging
      Trondheim, Sor-Trondelag Fylke, Norway
  • 2003–2008
    • University of California, San Diego
      • Department of Medicine
      San Diego, California, United States
  • 2002–2007
    • Medical University of Ohio at Toledo
      Toledo, Ohio, United States
  • 2006
    • Novartis Institutes for BioMedical Research
      Cambridge, Massachusetts, United States
    • University of Kansas
      • Department of Molecular and Integrative Physiology
      Kansas City, KS, United States
    • University of Colorado at Boulder
      • Department of Integrative Physiology
      Boulder, CO, United States