Abdominal obesity in COPD is associated with specific metabolic and functional phenotypes.

BACKGROUND: Abdominal obesity (AO) is linked to reduced health status and mortality. While it is known that AO is prevalent in chronic obstructive pulmonary disease (AO-COPD), the specific metabolic and functional consequences associated with AO-COPD remain understudied. METHODS: We studied 199 older adults with COPD and 168 control subjects with and without AO and assessed visceral adipose tissue (VAT) by dual-energy X-ray absorptiometry. VAT > 70th percentile of the control group qualified a subject as AO in a sex specific manner. We measured plasma concentrations and whole body production (WBP) rates of multiple amino acids to assess the metabolic profile. We assessed medical history, body composition by Dual-Energy X-ray Absorptiometry, muscle strength, and cognitive function. We performed statistics by analysis of covariance (p) and FDR (q) for multiple comparisons. RESULTS: AO-COPD subjects had 27% more VAT (q < 0.01) than AO-Control subjects despite correction for BMI. Branched-chain amino acid concentrations and WBP rates were generally elevated in AO-COPD but whole body clearance rate was only elevated in COPD. Metabolic syndrome comorbidities (p < 0.01) and systemic inflammation (P < 0.05) were most prevalent in the AO-COPD group. Muscle strength was reduced in COPD subjects (p < 0.001), but partially preserved when combined with AO. Cognitive dysfunction and mood disturbances were present in COPD subjects (p < 0.001) with worst performers in AO-COPD (q < 0.05). CONCLUSION: The presence of AO is associated with specific metabolic and functional phenotypes in COPD. Clinical trial registry Trial registration ClinicalTrials.gov. In the present paper, we report an analysis of the baseline measurements of COPD subjects and healthy controls from the study numbers: NCT01787682, NCT01787682, NCT02157844, NCT02082418, NCT02065141, NCT02770092, NCT02908425, NCT03159390, NCT02780219, NCT03327181, NCT03796455, NCT04928872, NCT04461236, NCT01173354, NCT01154400.

A low postabsorptive whole body protein balance is associated with markers of poor daily physical functioning in Chronic Obstructive Pulmonary Disease.

BACKGROUND & AIMS: Postabsorptive whole body protein kinetics are related to age, gender, body mass index (BMI), and habitual protein intake level. It is unclear how protein synthesis, breakdown, and postabsorptive protein balance rates are affected in Chronic Obstructive Pulmonary Disease (COPD)) and whether these relate to disease severity, lifestyle characteristics and poor daily functioning. METHODS: We studied 91 COPD (GOLD 1-4) and 56 age matched control subjects without COPD or other chronic or acute health disease/condition in the postabsorptive state and measured body composition by Dual-energy X-ray Absorptiometry, and disease severity and comorbidities by medical screening, blood analysis and questionnaires. We assessed whole body production rates of phenylalanine and tyrosine by pulse stable isotope tracer infusion to calculate whole body protein breakdown (PB) and hydroxylation of phenylalanine to tyrosine, representative of postabsorptive protein balance. We measured muscle and cognitive function, and physical performance by isokinetic dynamometry, cognitive assessments, and 6-min walk test. We assessed physical activity level, mood and dietary protein intake by questionnaires. We measured plasma enrichments by LC-MS/MS and statistics by Fisher's exact test or analysis of covariance. Data are mean [95% CI]. RESULTS: The COPD patients had moderate to severe airflow obstruction, multiple comorbidities, and elevated values for plasma high sensitivity c-reactive protein (hs-CRP) and glucose. Although PB (3630 [3361, 3900] vs 3504 [3297, 3711] umol/h, p = 0.1649) was not different, postabsorptive protein balance was lower in COPD patients (274.2 [242.4, 306.1] vs 212.9 [194.7, 231.0] umol/h, p < 0.0001), both compared to control subjects. A lower postabsorptive protein balance was associated with age (p < 0.0001) and higher levels for systolic blood pressure (p = 0.0051) and hs-CRP (p = 0.0046) but not with lung function. Furthermore, a lower postabsorptive protein balance level was associated with a lower intake of total calories and protein (p < 0.0001) and lower muscle strength (p = 0.0248), while only in COPD with a lower physical performance (p = 0.0343). We found no association with cognitive function or mood. For all subjects, a cumulative model that included group, gender, age, BMI, systolic blood pressure, hs-CRP, caloric intake, protein intake, and leg strength was able to explain 55% of the variation in postabsorptive protein balance. CONCLUSION: These data suggest that systemic inflammation, high blood pressure and low protein intake are risk factors of a lower postabsorptive protein balance in COPD patients. A lower postabsorptive protein balance is associated with markers of poor daily physical functioning.

Presence or Absence of Skeletal Muscle Dysfunction in Chronic Obstructive Pulmonary Disease is Associated With Distinct Phenotypes / La presencia o ausencia de disfunción muscular esquelética en la enfermedad pulmonar obstructiva crónica está asociada a fenotipos distintos

Introduction: Reduced skeletal muscle function and cognitive performance are common extrapulmonary features in Chronic Obstructive Pulmonary Disease (COPD) but their connection remains unclear. Whether presence or absence of skeletal muscle dysfunction in COPD patients is linked to a specific phenotype consisting of reduced cognitive performance, comorbidities and nutritional and metabolic disturbances needs further investigation.Methods: Thirty-seven patients with COPD (grade II–IV) were divided into two phenotypic cohorts based on the presence (COPD dysfunctional, n=25) or absence (COPD functional, n=12) of muscle dysfunction. These cohorts were compared to 28 healthy, age matched controls. Muscle strength (dynamometry), cognitive performance (Trail Making Test and STROOP Test), body composition (Dual-energy X-Ray Absorptiometry), habitual physical activity, comorbidities and mood status (questionnaires) were measured. Pulse administration of stable amino acid tracers was performed to measure whole body production rates.Results: Presence of muscle dysfunction in COPD was independent of muscle mass or severity of airflow obstruction but associated with impaired STROOP Test performance (p=0.04), reduced resting O2 saturation (p=0.003) and physical inactivity (p=0.01), and specific amino acid metabolic disturbances (enhanced leucine (p=0.02) and arginine (p=0.06) production). In contrast, COPD patients with normal muscle function presented with anxiety, increased fat mass, plasma glucose concentration, and metabolic syndrome related comorbidities (hypertension and dyslipidemia). (AU)

Introducción: El funcionamiento reducido del músculo esquelético y del rendimiento cognitivo son signos extrapulmonares comunes en la Enfermedad Pulmonar Obstructiva Crónica (EPOC), pero su conexión sigue sin estar clara. Es necesario investigar más si la presencia o ausencia de disfunción muscular esquelética en pacientes con EPOC está relacionada con un fenotipo específico que consiste en un rendimiento cognitivo reducido, comorbilidades y trastornos nutricionales y metabólicos.Métodos: Se separaron treinta y siete pacientes con EPOC (grado II-IV) en dos cohortes fenotípicas en función de la presencia (EPOC disfuncional, n=25) o ausencia (EPOC funcional, n=12) de disfunción muscular. Estas cohortes se compararon con 28 controles sanos, emparejados por edad. Se midieron la fuerza muscular (dinamometría), el rendimiento cognitivo (test de senderos y test de Stroop), la composición corporal (absorciometría de rayos X de doble energía), la actividad física habitual, las comorbilidades y el estado de ánimo (cuestionarios). Se administraron aminoácidos trazadores estables en pulsos para medir las tasas de producción de todo el cuerpo.Resultados: La presencia de disfunción muscular en la EPOC resultó ser independiente de la masa muscular o la gravedad de la obstrucción al flujo de aire, pero se asoció con afectación del rendimiento en el test de Stroop (p=0,04), una saturación en reposo de O2 disminuida (p=0,003) e inactividad física (p=0,01), y trastornos metabólicos de aminoácidos específicos [producción aumentada de leucina (p=0,02) y arginina (p=0,06)]. Por el contrario, los pacientes con EPOC con función muscular normal presentaron ansiedad, aumento de la masa grasa, de la concentración de glucosa en plasma y de las comorbilidades relacionadas con el síndrome metabólico (hipertensión y dislipidemia). (AU)

Presence or Absence of Skeletal Muscle Dysfunction in Chronic Obstructive Pulmonary Disease is Associated With Distinct Phenotypes.

INTRODUCTION: Reduced skeletal muscle function and cognitive performance are common extrapulmonary features in Chronic Obstructive Pulmonary Disease (COPD) but their connection remains unclear. Whether presence or absence of skeletal muscle dysfunction in COPD patients is linked to a specific phenotype consisting of reduced cognitive performance, comorbidities and nutritional and metabolic disturbances needs further investigation. METHODS: Thirty-seven patients with COPD (grade II-IV) were divided into two phenotypic cohorts based on the presence (COPD dysfunctional, n=25) or absence (COPD functional, n=12) of muscle dysfunction. These cohorts were compared to 28 healthy, age matched controls. Muscle strength (dynamometry), cognitive performance (Trail Making Test and STROOP Test), body composition (Dual-energy X-Ray Absorptiometry), habitual physical activity, comorbidities and mood status (questionnaires) were measured. Pulse administration of stable amino acid tracers was performed to measure whole body production rates. RESULTS: Presence of muscle dysfunction in COPD was independent of muscle mass or severity of airflow obstruction but associated with impaired STROOP Test performance (p=0.04), reduced resting O2 saturation (p=0.003) and physical inactivity (p=0.01), and specific amino acid metabolic disturbances (enhanced leucine (p=0.02) and arginine (p=0.06) production). In contrast, COPD patients with normal muscle function presented with anxiety, increased fat mass, plasma glucose concentration, and metabolic syndrome related comorbidities (hypertension and dyslipidemia). CONCLUSION: COPD patients with muscle dysfunction show characteristics of a cognitive - metabolic impairment phenotype, influenced by the presence of hypoxia, whereas those with normal muscle function present a phenotype of metabolic syndrome and mood disturbances.

Walking exercise alters protein digestion, amino acid absorption, and whole body protein kinetics in older adults with and without COPD.

Gut-related symptoms and an increase in markers of gut dysfunction have been observed in patients with chronic obstructive pulmonary disease (COPD). It remains unclear whether exercise, in relation to inducing hypoxia, plays a role in disturbances in protein digestion and amino acid absorption and whole body protein kinetics. Sixteen clinically stable patients with moderate-to-very severe COPD and 12 matched healthy subjects completed the study. Protein digestion and amino acid absorption, whole body protein kinetics were measured in the postabsorptive state via a continuous infusion of stable tracers in combination with orally administered stable tracer sips during 20 min of walking exercise and up to 4 h post exercise. In addition, concentrations of short-chain fatty acid (SCFA) and amino acids were measured. Patients with COPD completed one study day, walking at maximal speed, whereas healthy subjects completed two, one matched to the speed of a patient with COPD and one at maximal speed. The patients with COPD tolerated 20 min of vigorous intensity walking with an elevated heart rate (P < 0.0001) and substantial desaturation (P = 0.006). During exercise, we observed lower protein digestion (P = 0.04) and higher SCFA acetate (P = 0.04) and propionate (P = 0.02) concentrations on max speed study days, lower amino acid absorption (P = 0.004) in subjects with oxygen desaturation, and lower net protein breakdown (P = 0.03) and propionate concentrations (P = 0.04) in patients with COPD. During late recovery from exercise, amino acid absorption (P = 0.02) and net protein breakdown (P = 0.02) were lower in patients with COPD. Our data suggest that 20 min of walking exercise is sufficient to cause perturbations in gut function and whole body protein metabolism during and up to 4 h post exercise in older adults and in patients with COPD with exercise-induced hypoxia.NEW & NOTEWORTHY Gut function is disturbed in older adults with COPD. As exercise is the cornerstone of pulmonary rehabilitation in COPD, knowledge of the response of the gut to aerobic exercise is of importance.

Risk Factors for Postural and Functional Balance Impairment in Patients with Chronic Obstructive Pulmonary Disease.

Reduced balance function has been observed during balance challenging conditions in the chronic obstructive pulmonary disease (COPD) population and is associated with an increased risk of falls. This study aimed to examine postural balance during quiet standing with eyes open and functional balance in a heterogeneous group of COPD and non-COPD (control) subjects, and to identify risk factors underlying balance impairment using a large panel of methods. In COPD and control subjects, who were mostly overweight and sedentary, postural and functional balance were assessed using center-of-pressure displacement in anterior-posterior (AP) and medio-lateral (ML) directions, and the Berg Balance Scale (BBS), respectively. COPD showed 23% greater AP sway velocity (p = 0.049). The presence of oxygen therapy, fat mass, reduced neurocognitive function, and the presence of (pre)diabetes explained 71% of the variation in postural balance in COPD. Transcutaneous oxygen saturation, a history of exacerbation, and gait speed explained 83% of the variation in functional balance in COPD. Neurocognitive dysfunction was the main risk factor for postural balance impairment in the control group. This suggests that specific phenotypes of COPD patients can be identified based on their type of balance impairment.

Western diet-induced hepatic steatosis and alterations in the liver transcriptome in adult Brown-Norway rats.

BACKGROUND: The purpose of this study was to investigate the effects of sub-chronic high fat, high sucrose diet (also termed 'Westernized diet' or WD) feeding on the liver transcriptome during early nonalcoholic fatty liver disease (NAFLD) development. METHODS: Brown Norway male rats (9 months of age) were randomly assigned to receive ad libitum access to a control (CTL; 14 % kcal fat, 1.2 % sucrose by weight) diet or WD (42 % kcal from fat, 34 % sucrose by weight) for 6 weeks. RESULTS: Six weeks of WD feeding caused hepatic steatosis development as evidenced by the 2.25-fold increase in liver triacylglycerol content, but did not induce advanced liver disease (i.e., no overt inflammation or fibrosis) in adult Brown Norway rats. RNA deep sequencing (RNA-seq) revealed that 94 transcripts were altered in liver by WD feeding (46 up-, 48 down-regulated, FDR < 0.05). Specifically, the top differentially regulated gene network by WD feeding was 'Lipid metabolism, small molecular biochemistry, vitamin and mineral metabolism' (Ingenuity Pathway Analysis (IPA) score 61). The top-regulated canonical signaling pathway in WD-fed rats was the 'Superpathway of cholesterol biosynthesis' (10/29 genes regulated, p = 1.68E-17), which coincides with a tendency for serum cholesterol levels to increase in WD-fed rats (p = 0.09). Remarkably, liver stearoyl-CoA desaturase (Scd) mRNA expression was by far the most highly-induced transcript in WD-fed rats (approximately 30-fold, FDR = 0.01) which supports previous literature underscoring this gene as a crucial target during NAFLD development. CONCLUSIONS: In summary, sub-chronic WD feeding appears to increase hepatic steatosis development over a 6-week period but only induces select inflammation-related liver transcripts, mostly acute phase response genes. These findings continue to outline the early stages of NAFLD development prior to overt liver inflammation and advanced liver disease.

Oral adenosine-5'-triphosphate (ATP) administration increases blood flow following exercise in animals and humans.

INTRODUCTION: Extracellular adenosine triphosphate (ATP) stimulates vasodilation by binding to endothelial ATP-selective P2Y2 receptors; a phenomenon, which is posited to be accelerated during exercise. Herein, we used a rat model to examine how different dosages of acute oral ATP administration affected the femoral blood flow response prior to, during, and after an exercise bout. In addition, we performed a single dose chronic administration pilot study in resistance trained athletes. ANIMAL STUDY: Male Wistar rats were gavage-fed the body surface area, species adjusted human equivalent dose (HED) of either 100 mg (n=4), 400 mg (n=4), 1,000 mg (n=5) or 1,600 mg (n=5) of oral ATP as a disodium salt (Peak ATP®, TSI, Missoula, MT). Rats that were not gavage-fed were used as controls (CTL, n=5). Blood flow was monitored continuously: a) 60 min prior to, b) during and c) 90 min following an electrically-evoked leg-kicking exercise. Human Study: In a pilot study, 12 college-aged resistance-trained subjects were given 400 mg of ATP (Peak ATP®, TSI, Missoula, MT) daily for 12 weeks, and prior to an acute arm exercise bout at weeks 1, 4, 8, and 12. Ultrasonography-determined volumetric blood flow and vessel dilation in the brachial artery was measured at rest, at rest 30 minutes after supplementation, and then at 0, 3, and 6 minutes after the exercise. ANIMAL STUDY: Rats fed 1,000 mg HED demonstrated significantly greater recovery blood flow (p < 0.01) and total blood flow AUC values (p < 0.05) compared to CTL rats. Specifically, blood flow was elevated in rats fed 1,000 mg HED versus CTL rats at 20 to 90 min post exercise when examining 10-min blood flow intervals (p < 0.05). When examining within-group differences relative to baseline values, rats fed the 1,000 mg and 1,600 mg HED exhibited the most robust increases in blood flow during exercise and into the recovery period. Human study: At weeks 1, 8, and 12, ATP supplementation significantly increased blood flow, along with significant elevations in brachial dilation. CONCLUSIONS: Oral ATP administration can increase post-exercise blood flow, and may be particularly effective during exercise recovery.

Herbal adaptogens combined with protein fractions from bovine colostrum and hen egg yolk reduce liver TNF-α expression and protein carbonylation in Western diet feeding in rats.

BACKGROUND: We examined if a purported anti-inflammatory supplement (AF) abrogated Western-diet (WD)-induced liver pathology in rats. AF contained: 1) protein concentrates from bovine colostrum and avian egg yolk; 2) herbal adaptogens and antioxidants; and 3) acetyl-L-carnitine. METHODS: Nine month-old male Brown Norway rats were allowed ad libitum access to WD for 41-43 days and randomly assigned to WD + AF feeding twice daily for the last 31-33 days (n = 8), or WD and water-placebo feeding twice daily for the last 31-33 days (n = 8). Rats fed a low-fat/low-sucrose diet (CTL, n = 6) for 41-43 days and administered a water-placebo twice daily for the last 31-33 days were also studied. Twenty-four hours following the last gavage-feed, liver samples were analyzed for: a) select mRNAs (via RT-PCR) as well as genome-wide mRNA expression patterns (via RNA-seq); b) lipid deposition; and, c) protein carbonyl and total antioxidant capacity (TAC). Serum was also examined for TAC, 8-isoprostane and clinical chemistry markers. RESULTS: WD + AF rats experienced a reduction in liver Tnf-α mRNA (-2.8-fold, p < 0.01). Serum and liver TAC was lower in WD + AF versus WD and CTL rats (p < 0.05), likely due to exogenous antioxidant ingredients provided through AF as evidenced by a tendency for mitochondrial SOD2 mRNA to increase in WD + AF versus CTL rats (p = 0.07). Liver fat deposition nor liver protein carbonyl content differed between WD + AF versus WD rats, although liver protein carbonyls tended to be lower in WD + AF versus CTL rats (p = 0.08). RNA-seq revealed that 19 liver mRNAs differed between WD + AF versus WD when both groups were compared with CTL rats (+/- 1.5-fold, p < 0.01). Bioinformatics suggest that AF prevented WD-induced alterations in select genes related to the transport and metabolism of carbohydrates in favor of select genes related to lipid transport and metabolism. Finally, serum clinical safety markers and liver pathology (via lesion counting) suggests that chronic consumption of AF was well tolerated. CONCLUSIONS: AF supplementation elicits select metabolic, anti-inflammatory, and anti-oxidant properties which was in spite of WD feeding and persisted up to 24 hours after receiving a final dose.

Nucleus accumbens neuronal maturation differences in young rats bred for low versus high voluntary running behaviour.

We compared the nucleus accumbens (NAc) transcriptomes of generation 8 (G8), 34-day-old rats selectively bred for low (LVR) versus high voluntary running (HVR) behaviours in rats that never ran (LVR(non-run) and HVR(non-run)), as well as in rats after 6 days of voluntary wheel running (LVR(run) and HVR(run)). In addition, the NAc transcriptome of wild-type Wistar rats was compared. The purpose of this transcriptomics approach was to generate testable hypotheses as to possible NAc features that may be contributing to running motivation differences between lines. Ingenuity Pathway Analysis and Gene Ontology analyses suggested that 'cell cycle'-related transcripts and the running-induced plasticity of dopamine-related transcripts were lower in LVR versus HVR rats. From these data, a hypothesis was generated that LVR rats might have less NAc neuron maturation than HVR rats. Follow-up immunohistochemistry in G9-10 LVR(non-run) rats suggested that the LVR line inherently possessed fewer mature medium spiny (Darpp-32-positive) neurons (P < 0.001) and fewer immature (Dcx-positive) neurons (P < 0.001) than their G9-10 HVR counterparts. However, voluntary running wheel access in our G9-10 LVRs uniquely increased their Darpp-32-positive and Dcx-positive neuron densities. In summary, NAc cellularity differences and/or the lack of running-induced plasticity in dopamine signalling-related transcripts may contribute to low voluntary running motivation in LVR rats.

Comparing serum responses to acute feedings of an extensively hydrolyzed whey protein concentrate versus a native whey protein concentrate in rats: a metabolomics approach.

We examined how gavage feeding extensively hydrolyzed whey protein (WPH) versus a native whey protein concentrate (WPC) transiently affected serum biochemical profiles in rodents. Male Wistar rats (250-300 g) were 8 h fasted and subsequently fed isonitrogenous amounts of WPH or WPC, or remained unfed (control). Animals were sacrificed 15 min, 30 min, and 60 min post-gavage for serum extraction, and serum was analyzed using untargeted global metabolic profiling via gas chromatography/mass spectrometry (MS) and liquid chromatography/MS/MS platforms. We detected 333 serum metabolites amongst the experimental and control groups. Both WPH and WPC generally increased amino acids (1.2-2.8-fold), branched-chain amino acids (1.2-1.7-fold), and serum di- and oligo-peptides (1.1-2.7-fold) over the 60 min time course compared with control (q < 0.05). However, WPH increased lysine (false discovery rate using a q-value <0.05) and tended to increase isoleucine and valine 15 min post-feeding (q < 0.10) as well as aspartylleucine 30 min post-feeding compared with WPC (q < 0.05). While both protein sources led to a dramatic increase in free fatty acids compared with control (up to 6-fold increases, q < 0.05), WPH also uniquely resulted in a 30 min post-feeding elevation in free fatty acids compared with WPC (q < 0.05), an effect which may be due to the robust 30 min postprandial increase in epinephrine in the WPH cohort. These data provide a unique postprandial time-course perspective on how WPH versus WPC feedings affect circulating biochemicals and will guide future research comparing these 2 protein sources.

Sudden decrease in physical activity evokes adipocyte hyperplasia in 70- to 77-day-old rats but not 49- to 56-day-old rats.

The cessation of physical activity in rodents and humans initiates obesogenic mechanisms. The overall purpose of the current study was to determine how the cessation of daily physical activity in rats at 49-56 days of age and at 70-77 days of age via wheel lock (WL) affects adipose tissue characteristics. Male Wistar rats began voluntary running at 28 days old and were either killed at 49-56 days old or at 70-77 days old. Two cohorts of rats always had wheel access (RUN), a second two cohorts of rats had wheel access restricted during the last 7 days (7d-WL), and a third two cohorts of rats did not have access to a voluntary running wheel after the first 6 days of (SED). We observed more robust changes with WL in the 70- to 77-day-old rats. Compared with RUN rats, 7d-WL rats exhibited greater rates of gain in fat mass and percent body fat, increased adipocyte number, higher percentage of small adipocytes, and greater cyclin A1 mRNA in epididymal and perirenal adipose tissue. In contrast, 49- to 56-day-old rats had no change in most of the same characteristics. There was no increase in inflammatory mRNA expression in either cohort with WL. These findings suggest that adipose tissue in 70- to 77-day-old rats is more protected from WL than 49- to 56-day-old rats and responds by expansion via hyperplasia.

Phenotypic and molecular differences between rats selectively bred to voluntarily run high vs. low nightly distances.

The purpose of the present study was to partially phenotype male and female rats from generations 8-10 (G8-G10) that had been selectively bred to possess low (LVR) vs. high voluntary running (HVR) behavior. Over the first 6 days with wheels, 34-day-old G8 male and female LVRs ran shorter distances (P < 0.001), spent less time running (P < 0.001), and ran slower (P < 0.001) than their G8 male and female HVR counterparts, respectively. HVR and LVR lines consumed similar amounts of standard chow with or without wheels. No inherent difference existed in PGC-1α mRNA in the plantaris and soleus muscles of LVR and HVR nonrunners, although G8 LVR rats inherently possessed less NADH-positive superficial plantaris fibers compared with G8 HVR rats. While day 28 body mass tended to be greater in both sexes of G9-G10 LVR nonrunners vs. G9-G10 HVR nonrunners (P = 0.06), body fat percentage was similar between lines. G9-G10 HVRs had fat mass loss after 6 days of running compared with their prerunning values, while LVR did not lose or gain fat mass during the 6-day voluntary running period. RNA deep sequencing efforts in the nucleus accumbens showed only eight transcripts to be >1.5-fold differentially expressed between lines in HVR and LVR nonrunners. Interestingly, HVRs presented less Oprd1 mRNA, which ties in to potential differences in dopaminergic signaling between lines. This unique animal model provides further evidence as to how exercise may be mechanistically regulated.