- Left ventricle transcriptomic analysis reveals connective tissue accumulation associates with initial age-dependent decline in V̇O2peak from its lifetime apex. [Journal Article]
- PGPhysiol Genomics 2016 Dec 02; :physiolgenomics.00083.2016
- Peak oxygen consumption (V̇O2peak) strongly predicts morbidity and mortality better than other established risk factors, yet mechanisms associated with its age-associated decline are unknown. Our lab...
Peak oxygen consumption (V̇O2peak) strongly predicts morbidity and mortality better than other established risk factors, yet mechanisms associated with its age-associated decline are unknown. Our lab has shown that V̇O2peak first begins to decrease at the same age of 19-20 weeks old in both sedentary and wheel-running, female Wistar rats (Toedebusch et al., Physiol Genomics. 48:101-15, 2016). Here, we employed a total systemic approach using unsupervised interrogation of mRNA with RNA-sequencing. The purpose of our study was to analyze transcriptomic profiles from both sedentary (SED) and wheel-running (RUN) conditions as a strategy to identify pathways in the left ventricle that may contribute to the initial reductions in V̇O2peak occurring between 19 and 27 weeks of age. Transcriptomic comparisons were made within both SED and RUN rats between 19 and 27 wks (n= 5-8). Analysis of mRNAs shared in SED and RUN between 19 and 27 wks found 17 up-regulated (e.g. Adra1d, Rpl17, Xpo7) and 8 down-regulated (e.g. Cdo1, Ctfg, Sfrp1) mRNAs, at 19 wks, respectively. Furthermore, bioinformatics analysis of mRNAs common to SED and RUN produced networks suggestive of increased connective tissue development at 27 vs. 19 wks. Additionally, Ctfg mRNA was negatively associated with V̇O2peak in both SED and RUN (p< 0.05). In summary, transcriptomic analysis revealed mRNAs and networks associated with increased connective tissue development, decreased α-adrenergic activity, and decreased protein translation in the left ventricle that could, in part, potentially influence the initiation of the lifelong reduction in V̇O2peak, independent of physical activity levels.
- Partial deficiency of CTRP12 alters hepatic lipid metabolism. [Journal Article]
- PGPhysiol Genomics 2016 Nov 04; :physiolgenomics.00111.2016
- Secreted hormones play pivotal roles in tissue crosstalk to maintain physiologic blood glucose and lipid levels. We previously showed that C1q/TNF-related protein 12 (CTRP12) is a novel secreted prot...
Secreted hormones play pivotal roles in tissue crosstalk to maintain physiologic blood glucose and lipid levels. We previously showed that C1q/TNF-related protein 12 (CTRP12) is a novel secreted protein involved in regulating glucose metabolism whose circulating levels are reduced in obese and insulin-resistant mouse models. Its role in lipid metabolism, however, is unknown. Using a novel heterozygous mouse model, we show that the loss of a single copy of the Ctrp12 gene (also known as Fam132a and adipolin) affects whole-body lipid metabolism. In Ctrp12 (+/-) male mice fed a control low-fat diet, hepatic fat oxidation was upregulated while hepatic VLDL-triglyceride secretion was reduced relative to wild-type (WT) littermates. When challenged with a high-fat diet, Ctrp12 (+/-) male mice had impaired lipid clearance in response to acute lipid gavage, reduced hepatic triglyceride secretion, and greater steatosis with higher liver triglyceride and cholesterol levels. Unlike male mice, Ctrp12 (+/-) female mice fed a control low-fat diet were indistinguishable from WT littermates. When obesity was induced by high-fat feeding, Ctrp12 (+/-) female mice developed mild insulin resistance with impaired insulin tolerance. In contrast to male mice, hepatic triglyceride secretion was increased in Ctrp12 (+/-) female mice fed a high-fat diet. Thus, in different dietary and metabolic contexts, loss of a single Ctrp12 allele affects glucose and lipid metabolism in a sex-dependent manner, highlighting the importance of genetic and environmental determinants of metabolic phenotypes.
- Pattern analysis uncovers a chronic ethanol-induced disruption of the switch-like dynamics of C/EBP-β and C/EBP-α genome-wide binding during liver regeneration. [Journal Article]
- PGPhysiol Genomics 2016 Nov 04; :physiolgenomics.00097.2016
- Chronic ethanol intake impairs liver regeneration through a system-wide alteration in the regulatory networks driving the response to injury. Our study focused on the initial phase of response to 2/3...
Chronic ethanol intake impairs liver regeneration through a system-wide alteration in the regulatory networks driving the response to injury. Our study focused on the initial phase of response to 2/3(rd) partial hepatectomy (PHx) to investigate how adaptation to chronic ethanol intake affects the genome-wide binding profiles of the transcription factors C/EBP-β and C/EBP-α. These factors participate in complementary and often opposing functions for maintaining cellular differentiation, regulating metabolism, and governing cell growth during liver regeneration. We analyzed ChIP-seq data using a comparative pattern count (COMPACT) analysis, which exhaustively enumerates temporal patterns of discretized binding profiles to identify dominant as well as subtle patterns that may not be apparent using conventional clustering analyses. We found that adaptation to chronic ethanol intake significantly alters the genome-wide binding profile of C/EBP-β and C/EBP-α prior to and following PHx. A subset of these ethanol-induced changes include C/EBP-β binding to promoters of genes involved in the pro-fibrogenic TGF-β pathway, and both C/EBP-β and C/EBP-α binding to promoters of genes involved in the cell cycle, apoptosis, homeostasis, and metabolic processes. The shift in C/EBP binding loci, coupled with an ethanol-induced increase in C/EBP-β binding at 6 hours post-resection, indicates that ethanol adaptation may change both the amount and nature of C/EBP binding post-resection. Taken together, our results suggest that chronic ethanol consumption leads to a spatially and temporally reorganized activity at many genomic loci, resulting in a shift in the dynamic balance and coordination of cellular processes underlying regenerative response.
- Biological Roles of microRNAs in the Control of Insulin Secretion and Action. [Journal Article]
- PGPhysiol Genomics 2016 Nov 04; :physiolgenomics.00079.2016
- MicroRNAs (miRNAs) are intracellular and circulating molecular components contributing to genome expression control through binding mRNA targets, which generally results in downregulated mRNA express...
MicroRNAs (miRNAs) are intracellular and circulating molecular components contributing to genome expression control through binding mRNA targets, which generally results in downregulated mRNA expression. One miRNA can target several mRNAs and one transcript can be targeted by several miRNAs, resulting in complex fine tuning of regulation of gene networks and signaling pathways. miRNAs regulate metabolism, adipocyte differentiation, pancreatic development, β-cell mass, insulin biosynthesis, secretion and signaling and their role in diabetes and obesity is emerging. Their pathophysiological effects are essentially dependent on cellular co-expression with their mRNA targets, which can show tissue-specific transcriptional responses to disease conditions and environmental challenges. Current knowledge of miRNA biology and their impact in the pathogenesis of diabetes and obesity is based on experimental data documenting miRNA expression generally in single tissue types which can be correlated with expression of target mRNAs to integrate miRNA in functional pathways and gene networks. Here we present results from the most significant studies dealing with miRNA function in liver, fat, skeletal muscle and endocrine pancreas and their implication in diabetes and obesity.
- Effects of dietary forage and calf starter on ruminal pH and transcriptomic adaptation of the rumen epithelium in Holstein calves during the weaning transition. [Journal Article]
- PGPhysiol Genomics 2016 Nov 01; 48(11):803-809
- We investigated the relationship between ruminal pH and transcriptomic adaptation of the rumen epithelium (RE) of calves fed calf starter with and without forage during the weaning transition. Holste...
We investigated the relationship between ruminal pH and transcriptomic adaptation of the rumen epithelium (RE) of calves fed calf starter with and without forage during the weaning transition. Holstein calves were assigned to groups fed calf starter either with forage (HAY group, n = 3) or without forage (CON group, n = 4). Ruminal pH was measured continuously, and rumen fluid and epithelium were collected 3 wk after weaning. mRNA expression profiles of the RE were examined by one-color microarray. Differentially expressed genes (DEGs) were investigated using the Ingenuity Pathway Analysis (IPA). Mean and maximum ruminal pH were significantly (P < 0.05) higher, and the duration of pH < 5.8 during 1 day was significantly (P < 0.05) shorter, in the HAY group. The proportion of ruminal acetate and the acetate-to-propionate ratio were significantly (P < 0.05) lower in the CON group. DEGs encoding transcription regulators (SREBP1), insulin-like growth factor binding proteins (IGFBP7 and CTGF), ketogenic enzymes (HMGCL, BDH1, and BDH2), and a transporter (SLC16A3) were identified (P < 0.05) between the two groups. A growth factor (TGFB1) and signaling pathway (EGF and EGFR) were activated as upstream regulators. These results suggest that dietary forage alleviates ruminal acidosis, and the decrease in ruminal pH may damage the RE, leading to changes in gene expression to repair the damage. Furthermore, rumen development may be regulated by growth factor (TGFB1) and signaling pathways (EGF and IGFBP) for adaptation to feeding on calf starter with and without forage during the weaning transition.
- Selection-, age-, and exercise-dependence of skeletal muscle gene expression patterns in a rat model of metabolic fitness. [Journal Article]
- PGPhysiol Genomics 2016 Nov 01; 48(11):816-825
- Intrinsic aerobic exercise capacity can influence many complex traits including obesity and aging. To study this connection we established two rat lines by divergent selection of untrained aerobic ca...
Intrinsic aerobic exercise capacity can influence many complex traits including obesity and aging. To study this connection we established two rat lines by divergent selection of untrained aerobic capacity. After 32 generations the high capacity runners (HCR) and low capacity runners (LCR) differed in endurance running distance and body fat, blood glucose, other health indicators, and natural life span. To understand the interplay among genetic differences, chronological age, and acute exercise we performed microarray-based gene expression analyses in skeletal muscle with a 2×2×2 design to simultaneously compare HCR and LCR, old and young animals, and rest and exhaustion. Transcripts for mitochondrial function are expressed higher in HCRs than LCRs at both rest and exhaustion and for both age groups. Expression of cell adhesion and extracellular matrix genes tend to decrease with age. This and other age effects are more prominent in LCRs than HCRs, suggesting that HCRs have a slower aging process and this may be partly due to their better metabolic health. Strenuous exercise mainly affects transcription regulation and cellular response. The effects of any one factor often depend on the other two. For example, there are ∼140 and ∼110 line-exercise "interacting" genes for old and young animals, respectively. Many genes highlighted in our study are consistent with prior reports, but many others are novel. The gene- and pathway-level statistics for the main effects, either overall or stratified, and for all possible interactions, represent a rich reference dataset for understanding the interdependence among lines, aging, and exercise.
- Transcriptome assessment of the Pompe (Gaa-/-) mouse spinal cord indicates widespread neuropathology. [Journal Article]
- PGPhysiol Genomics 2016 Nov 01; 48(11):785-794
- Pompe disease, caused by deficiency of acid alpha-glucosidase (GAA), leads to widespread glycogen accumulation and profound neuromuscular impairments. There has been controversy, however, regarding t...
Pompe disease, caused by deficiency of acid alpha-glucosidase (GAA), leads to widespread glycogen accumulation and profound neuromuscular impairments. There has been controversy, however, regarding the role of central nervous system pathology in Pompe motor dysfunction. We hypothesized that absence of GAA protein causes progressive activation of neuropathological signaling, including pathways associated with cell death. To test this hypothesis, genomic data (Affymetrix Mouse Gene Array 2.0ST) from the midcervical spinal cord in 6 and 16 mo old Pompe (Gaa(-/-)) mice were evaluated (Broad Institute Molecular Signature Database), along with spinal cord histology. The midcervical cord was selected because it contains phrenic motoneurons, and phrenic-diaphragm dysfunction is prominent in Pompe disease. Several clinically important themes for the neurologic etiology of Pompe disease emerged from this unbiased genomic assessment. First, pathways associated with cell death were strongly upregulated as Gaa(-/-) mice aged, and motoneuron apoptosis was histologically verified. Second, proinflammatory signaling was dramatically upregulated in the Gaa(-/-) spinal cord. Third, many signal transduction pathways in the Gaa(-/-) cervical cord were altered in a manner suggestive of impaired synaptic function. Notably, glutamatergic signaling pathways were downregulated, as were "synaptic plasticity pathways" including genes related to neuroplasticity. Fourth, many genes and pathways related to cellular metabolism are dysregulated. Collectively, the data unequivocally confirm that systemic absence of GAA induces a complex neuropathological cascade in the spinal cord. Most importantly, the results indicate that Pompe is a neurodegenerative condition, and this underscores the need for early therapeutic intervention capable of targeting the central nervous system.
- Association of ADAMTS7 gene polymorphism with cardiovascular survival in coronary artery disease. [Journal Article]
- PGPhysiol Genomics 2016 Nov 01; 48(11):810-815
- Recent genetic studies have revealed an association between polymorphisms at the ADAMTS7 gene locus and coronary artery disease (CAD) risk. Functional studies have shown that a CAD-associated polymor...
Recent genetic studies have revealed an association between polymorphisms at the ADAMTS7 gene locus and coronary artery disease (CAD) risk. Functional studies have shown that a CAD-associated polymorphism (rs3825807) affects ADAMTS7 maturation and vascular smooth muscular cell (VSMC) migration. Here, we tested whether ADAMTS7 (A/G) SNP is associated with cardiovascular (CV) survival in patients with established CAD. A cohort of 1,128 patients with angiographic proven CAD, who were followed up prospectively for a mean follow-up period of 63 (range 6-182) mo, were genotyped for rs3825807 A/G. Survival statistics (Cox regression) compared heterozygous (AG) and wild-type (AA) with the reference homozygous GG. Kaplan-Meier (K-M) survival curves were performed according to ADAMTS7 genotypes for CV mortality. Results showed that 47.3% of patients were heterozygous (AG), 36.5% were homozygous for the wild-type allele (AA) and only 16.2% were homozygous for the GG genotype. During the follow-up period, 109 (9.7%) patients died, 77 (6.8%) of CV causes. Survival analysis showed that AA genotype was an independent risk factor for CV mortality compared with reference genotype GG (HR = 2.7, P = 0.025). At the end of follow-up, the estimated survival probability (K-M) was 89.8% for GG genotype, 82.2% for AG and 72.3% for AA genotype (P = 0.039). Carriage of the mutant G allele of the ADAMTS7 gene was associated with improved CV survival in patients with documented CAD. The native overfunctional ADAMTS7 allele (A) may accelerate VSMC migration and lead to neointimal thickening, atherosclerosis progression and acute plaque events. ADAMTS7 gene should be further explored in CAD for risk prediction, mechanistic and therapeutic goals.
- Immune and inflammatory responses to freediving calculated from leukocyte gene expression profiles. [Journal Article]
- PGPhysiol Genomics 2016 Nov 01; 48(11):795-802
- Freedivers hold their breath while diving, causing blood oxygen levels to decrease (hypoxia) while carbon dioxide increases (hypercapnia). Whereas blood gas changes are presumably involved in the pro...
Freedivers hold their breath while diving, causing blood oxygen levels to decrease (hypoxia) while carbon dioxide increases (hypercapnia). Whereas blood gas changes are presumably involved in the progression of respiratory diseases, less is known about their effect on healthy individuals. Here we have used gene expression profiling to analyze elite athletes' immune and inflammatory responses to freediving. Blood was collected before and 1 and 3 h after a series of maximal dynamic and static freediving apneas in a pool, and peripheral blood gene expression was mapped on genome-wide microarrays. Fractions of phenotypically distinct immune cells were computed by deconvolution of the gene expression data using Cibersort software. Changes in gene activity and associated biological pathways were determined using R and GeneGo software. The results indicated a temporary increase of neutrophil granulocytes, and a decrease of cytotoxic lymphocytes; i.e., CD8+ T cells and resting NK cells. Biological pathway associations indicated possible protective reactions: genes involved in anti-inflammatory responses to proresolving lipid mediators were upregulated, whereas central factors involved in granule-mediated lymphocyte cytotoxicity were downregulated. While it remains unresolved whether freediving alters the immune system's defensive function, these results provide new insight into leukocyte responses and the protection of homeostasis in healthy athletes.
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- Comparative transcriptomic analysis identifies genes differentially expressed in human epicardial progenitors and hiPSC-derived cardiac progenitors. [Journal Article]
- PGPhysiol Genomics 2016 Nov 1; 48(11):771-784
- Regenerative therapies hold great potential to change the treatment paradigm for cardiac diseases. Human cardiac progenitor cells can be used for drug discovery in this area and also provide a renewa...
Regenerative therapies hold great potential to change the treatment paradigm for cardiac diseases. Human cardiac progenitor cells can be used for drug discovery in this area and also provide a renewable source of cardiomyocytes. However, a better understanding of their characteristics is critical for interpreting data obtained from drug screening using these cells. In the present study, we performed global transcriptional analysis of two important sources of cardiac progenitors, i.e., patient epicardium-derived cells (EPDCs) and cardiac progenitor cells (CPCs) derived from human induced pluripotent stem cells. In addition, we also compared the gene expression profiles of these cells when they were cultured under normoxic and hypoxic conditions. We identified 3,289 mRNAs that were differentially expressed between EPDCs and CPCs. Gene ontology annotation and pathway enrichment analyses further revealed possible unique functions of these two cell populations. Notably, the impact of hypoxia vs normoxia on gene expression was modest and only a few genes (e.g., AK4, ALDOC, BNIP3P1, PGK1, and SLC2A1) were upregulated in EPDCs and CPCs after the cells were exposed to low oxygen for 24 h. Finally, we also performed a focused analysis of the gene expression patterns of a predefined set of 92 paracrine factors. We identified 30 of these genes as differentially expressed, and 29 were expressed at higher levels in EPDCs compared with CPCs. Taken together, the results of the present study advance our understanding of the transcriptional programs in EPDCs and CPCs and highlights important differences and similarities between these cell populations.