Gene expression profiling in a rat model of monocrotaline-induced heart failure
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE72701 | GEO | 2015/12/01
SECONDARY ACCESSION(S): PRJNA294692
REPOSITORIES: GEO
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Project description:Cancer cachexia is a prevalent and often fatal wasting condition that cannot be fully reversed with nutritional interventions. Muscle atrophy is a central component of the syndrome, but the mechanisms whereby cancer leads to skeletal muscle atrophy are not well understood. We performed single nucleus multi-omics on skeletal muscles from a mouse model of cancer cachexia and profiled the molecular changes in cachexic muscle. Our results revealed the activation of a denervation-induced gene program that upregulates the transcription factor myogenin. Further studies showed that a myogenin-myostatin pathway promotes muscle atrophy in response to cancer cachexia. shRNA inhibition of myogenin or inhibition of myostatin through overexpression of its endogenous inhibitor follistatin prevented cancer cachexia-induced muscle atrophy in mice. Our findings uncover a molecular basis of cancer cachexia-induced muscle atrophy and highlight potential therapeutic targets for this disorder.
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Project description:Altered myocardial gene expression from heart failure (HF) has mostly been identified by single-point analysis of end-stage disease. This may miss earlier changes in gene expression that are transient and/or directionally opposite to those observed later. By sampling left ventricular myocardial tissue at different time points in a mouse model of cardiomyopathy, we examined differentially expressed transcripts between non-failing controls, early-HF (2 and 3 days after cardiac insult), peak-HF (10 days) and after recovery from HF (28 days). As a results, we found that gene expression followed varying patterns: Downregulation of metabolic pathways occurred early and was sustained into late stage-HF. In contrast, most signaling pathways undergo a complex biphasic pattern: Calcium signaling, p53, apoptosis and MAP-kinase pathways displayed a bi-directional response, declining early but rising late, while NF-κB-related transcription displayed the opposite pattern. The HF-induced transcriptomic changes were reversed after recovery at 28 days. We conclude that the myocardial transcriptome in evolving HF displays distinct and dynamic transcript clusters. Therapies targeting different phases of HF should consider these dynamic features when identifying high-value targets. Mice expressing mutated estrogen receptor-coupled Cre under transcriptional control of cardiac-specific myosin heavy chain (MerCreMer, MCM, 005650;Jackson Laboratories, Bar Harbor, ME) were back-crossed for >10 generations with C57Bl6/J. Transient cardiomyopathy develops in these mice following 5 day exposure to tamoxifen free base (T5648, Sigma), with peak dysfunction at day 10 and full recovery after 4 weeks. Full transcriptome analyses were generated from flash-frozen left ventricular myocardium at different time points (control = baseline, day 2, day 3, day 10, and day 28).
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Project description:The study sought to determine the global miRNA profile of ventricles during early and end-stage hypertrophic cardiomyopathy in a severe double mutant mouse model of the disease. MicroRNA expression profiles of ventricles of transgenic mice with a mutation in both the myosin heavy chain gene (MYH7 Arg403Gln) and cardiac troponin I gene (TNNI3 Ser203Gln) and of non-transgenic mice were determined using Rodent TaqMan Low Density miRNA Arrays A v2.0 (TLDA, Life Technologies). MicroRNA profiles were measured at 10 days of age and 16 days of age, in 3 biological replicates. qRT-PCR analysis of microRNAs of ventricles of three transgenic mice and three non-transgenic mice age 10 days, and three transgenic mice and three non-transgenic mice age 16 days. 450 ng RNA was reverse transcribed, without pre-amplification, using TaqMan MicroRNA Reverse Transcription Kit and Megaplex RT Primers rodent pool A (Life Technologies). Complementary DNA (cDNA) was amplified using a TaqMan rodent microRNA A Array v2.0 (Life Technologies) with TaqMan Universal PCR Master Mix on an ABI 7900HT Sequence Detection System.
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