UCP1 Knockin Induces Lipid Dynamics and Transcriptional Programs in the Skeletal Muscles of Pigs.
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ABSTRACT:
SUBMITTER: Xu Z
PROVIDER: S-EPMC8790096 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1?) is a chief activator of mitochondrial and metabolic programs and protects against atrophy in skeletal muscle (skm). Here we tested whether PGC-1? overexpression could restructure the transcriptome and metabolism of primary cultured human skm cells, which display a phenotype that resembles the atrophic phenotype. An oligonucleotide microarray analysis was used to reveal the effects of PGC-1? on the whole transcriptome. Fifty-three different genes showed altered expression in response to PGC-1?: 42 upregulated and 11 downregulated. The main gene ontologies (GO) associated with the upregulated genes were mitochondrial components and processes and this was linked with an increase in COX activity, an indicator of mitochondrial content. Furthermore, PGC-1? enhanced mitochondrial oxidation of palmitate and lactate to CO(2), but not glucose oxidation. The other most significantly associated GOs for the upregulated genes were chemotaxis and cytokine activity, and several cytokines, including IL-8/CXCL8, CXCL6, CCL5 and CCL8, were within the most highly induced genes. Indeed, PGC-1? highly increased IL-8 cell protein content. The most upregulated gene was PVALB, which is related to calcium signaling. Potential metabolic regulators of fatty acid and glucose storage were among mainly regulated genes. The mRNA and protein level of FITM1/FIT1, which enhances the formation of lipid droplets, was raised by PGC-1?, while in oleate-incubated cells PGC-1? increased the number of smaller lipid droplets and modestly triglyceride levels, compared to controls. CALM1, the calcium-modulated ? subunit of phosphorylase kinase, was downregulated by PGC-1?, while glycogen phosphorylase was inactivated and glycogen storage was increased by PGC-1?. In conclusion, of the metabolic transcriptome deficiencies of cultured skm cells, PGC-1? rescued the expression of genes encoding mitochondrial proteins and FITM1. Several myokine genes, including IL-8 and CCL5, which are known to be constitutively expressed in human skm cells, were induced by PGC-1?.
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Project description:BackgroundIn mammals, cold exposure induces browning of white adipose tissue (WAT) and alters WAT gene expression and lipid metabolism to boost adaptive thermogenesis and maintain body temperature. Understanding the lipidomic and transcriptomic profiles of WAT upon cold exposure provides insights into the adaptive changes associated with this process.ResultsHere, we applied mass spectrometry and RNA sequencing (RNA-seq) to provide a comprehensive resource for describing the lipidomic or transcriptome profiles in cold-induced inguinal WAT (iWAT). We showed that short-term (3-day) cold exposure induces browning of iWAT, increases energy expenditure, and results in loss of body weight and fat mass. Lipidomic analysis shows that short-term cold exposure leads to dramatic changes of the overall composition of lipid classes WAT. Notably, cold exposure induces significant changes in the acyl-chain composition of triacylglycerols (TAGs), as well as the levels of glycerophospholipids and sphingolipids in iWAT. RNA-seq and qPCR analysis suggests that short-term cold exposure alters the expression of genes and pathways involved in fatty acid elongation, and the synthesis of TAGs, sphingolipids, and glycerophospholipids. Furthermore, the cold-induced lipid dynamics and gene expression pathways in iWAT are contrary to those previously observed in metabolic syndrome, neurodegenerative disorders, and aging, suggesting beneficial effects of cold-induced WAT browning on health and lifespan.ConclusionWe described the significant alterations in the composition of glyphospholipids, glycerolipids, and sphingolipids and expression of genes involved in thermogenesis, fatty acid elongation, and fatty acid metabolism during the response of iWAT to short-term cold exposure. We also found that some changes in the levels of specific lipid species happening after cold treatment of iWAT are negatively correlated to metabolic diseases, including obesity and T2D.
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Project description:Brown and beige adipose tissue may represent important therapeutic targets for the treatment of diabetes and obesity as these organs dissipate nutrient energy as heat through the thermogenic uncoupling protein 1 (UCP1). While mice are commonly used to mimic the potential effects of brown/beige adipose tissue that may act in human metabolism, new animal models are edging into the market for translational medicine. Pigs reflect human metabolism better than mice in multiple parameters such as obesity-induced hyperglycemia, cholesterol profiles and energy metabolism. Recently, it was reported that energy expenditure and body temperature in pigs is induced by the hormone leptin, and that leptin's action is mediated by UCP1 in adipose tissue. Given the tremendous importance of identifying molecular mechanisms for targeting therapeutics, we critically examine the evidence supporting the presence of UCP1 in pigs and conclude that methodological shortcomings prevent an unequivocal claim for the presence of UCP1 in pigs. Despite this, we believe that leptin's effects on energy expenditure in pigs are potentially more transformative to human medicine in the absence of UCP1, as adult and obese humans possess only minor amounts of UCP1. In general, we propose that the biology of new animal models requires attention to comparative studies with humans given the increasing amount of genomic information for various animal species.
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Project description:In the present study, we conducted transcriptomics on skeletal muscle from 6-month-old UCP1 KI and wild-type (WT) pigs to explore the transcriptional programs induced by adipocyte-specific UCP1 overexpression in skeletal muscle
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Project description:Aging significantly affects the cardiac muscle (CM) and skeletal muscles (SM). Since the aging process of CM and SM may be different, high throughput RNA sequencing was performed using CM and SM in different age conditions to evaluate the expression profiles of messenger RNA (mRNA), long non-coding RNA (lncRNA), micro RNA (miRNA), and circular (circRNA). Several mRNAs, lncRNAs, and miRNAs were highly expressed and consistently appeared in both ages in one of the two muscle tissues. Gene ontology (GO) annotation described that these genes were required for maintaining normal biological functions of CM and SM tissues. Furthermore, 26 mRNAs, 4 lncRNAs, 22 miRNAs, and 26 circRNAs were differentially expressed during cardiac muscle aging. Moreover, 81 mRNAs, 5 lncRNAs, 79 miRNAs, and 62 circRNAs were differentially expressed during aging of skeletal muscle. When comparing the expression profiles of CM and SM during aging, the senescence process in CM and SM was found to be fundamentally different. In addition, we assessed multi-group cooperative control relationships and constructed circRNA-miRNA-mRNA co-expression networks in muscular aging. In conclusion, our findings will contribute to the understanding of muscular aging and provide a foundation for future studies on the molecular mechanisms underlying muscular aging.
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Project description:Muscle degenerative diseases such as Duchenne Muscular Dystrophy are incurable and treatment options are still restrained. Understanding the mechanisms and factors responsible for muscle degeneration and regeneration will facilitate the development of novel therapeutics. Several recent studies have demonstrated that Galectin-1 (Gal-1), a carbohydrate-binding protein, induces myoblast differentiation and fusion in vitro, suggesting a potential role for this mammalian lectin in muscle regenerative processes in vivo. However, the expression and localization of Gal-1 in vivo during muscle injury and repair are unclear. We report the expression and localization of Gal-1 during degenerative-regenerative processes in vivo using two models of muscular dystrophy and muscle injury. Gal-1 expression increased significantly during muscle degeneration in the murine mdx and in the canine Golden Retriever Muscular Dystrophy animal models. Compulsory exercise of mdx mouse, which intensifies degeneration, also resulted in sustained Gal-1 levels. Furthermore, muscle injury of wild-type C57BL/6 mice, induced by BaCl(2) treatment, also resulted in a marked increase in Gal-1 levels. Increased Gal-1 levels appeared to localize both inside and outside the muscle fibers with significant extracellular Gal-1 colocalized with infiltrating CD45(+) leukocytes. By contrast, regenerating muscle tissue showed a marked decrease in Gal-1 to baseline levels. These results demonstrate significant regulation of Gal-1 expression in vivo and suggest a potential role for Gal-1 in muscle homeostasis and repair.
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Project description:MicroRNAs (miRNAs) are short, single-stranded non-coding RNAs that repress their target genes by binding their 3' UTRs. These RNAs play critical roles in myogenesis. To gain knowledge about miRNAs involved in the regulation of myogenesis, porcine longissimus muscles were collected from 18 developmental stages (33-, 40-, 45-, 50-, 55-, 60-, 65-, 70-, 75-, 80-, 85-, 90-, 95-, 100- and 105-day post-gestation fetuses, 0 and 10-day postnatal piglets and adult pigs) to identify miRNAs using Solexa sequencing technology. We detected 197 known miRNAs and 78 novel miRNAs according to comparison with known miRNAs in the miRBase (release 17.0) database. Moreover, variations in sequence length and single nucleotide polymorphisms were also observed in 110 known miRNAs. Expression analysis of the 11 most abundant miRNAs were conducted using quantitative PCR (qPCR) in eleven tissues (longissimus muscles, leg muscles, heart, liver, spleen, lung, kidney, stomach, small intestine and colon), and the results revealed that ssc-miR-378, ssc-miR-1 and ssc-miR-206 were abundantly expressed in skeletal muscles. During skeletal muscle development, the expression level of ssc-miR-378 was low at 33 days post-coitus (dpc), increased at 65 and 90 dpc, peaked at postnatal day 0, and finally declined and maintained a comparatively stable level. This expression profile suggested that ssc-miR-378 was a new candidate miRNA for myogenesis and participated in skeletal muscle development in pigs. Target prediction and KEGG pathway analysis suggested that bone morphogenetic protein 2 (BMP2) and mitogen-activated protein kinase 1 (MAPK1), both of which were relevant to proliferation and differentiation, might be the potential targets of miR-378. Luciferase activities of report vectors containing the 3'UTR of porcine BMP2 or MAPK1 were downregulated by miR-378, which suggested that miR-378 probably regulated myogenesis though the regulation of these two genes.
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Project description:BACKGROUND:A stereotyped array of body wall muscles enables precision and stereotypy of animal movements. In Drosophila, each syncytial muscle forms via fusion of one founder cell (FC) with multiple fusion competent myoblasts (FCMs). The specific morphology of each muscle, i.e. distinctive shape, orientation, size and skeletal attachment sites, reflects the specific combination of identity transcription factors (iTFs) expressed by its FC. Here, we addressed three questions: Are FCM nuclei naive? What is the selectivity and temporal sequence of transcriptional reprogramming of FCMs recruited into growing syncytium? Is transcription of generic myogenic and identity realisation genes coordinated during muscle differentiation? RESULTS:The tracking of nuclei in developing muscles shows that FCM nuclei are competent to be transcriptionally reprogrammed to a given muscle identity, post fusion. In situ hybridisation to nascent transcripts for FCM, FC-generic and iTF genes shows that this reprogramming is progressive, beginning by repression of FCM-specific genes in fused nuclei, with some evidence that FC nuclei retain specific characteristics. Transcription of identity realisation genes is linked to iTF activation and regulated at levels of both transcription initiation rate and period of transcription. The generic muscle differentiation programme is activated independently. CONCLUSIONS:Transcription reprogramming of fused myoblast nuclei is progressive, such that nuclei within a syncytial fibre at a given time point during muscle development are heterogeneous with regards to specific gene transcription. This comprehensive view of the dynamics of transcriptional (re)programming of post-mitotic nuclei within syncytial cells provides a new framework for understanding the transcriptional control of the lineage diversity of multinucleated cells.
| S-EPMC5466778 | biostudies-literature
Project description:BACKGROUND: Myoblasts undergo major changes in their plasma membrane during the initial steps of skeletal muscle differentiation, including major alterations in the distribution of cholesterol. Cholesterol is involved in crucial membrane functions, such as fluidity, and permeability, and in the organization of specialized membrane microdomains (or lipid rafts). We have previously shown that alterations in cholesterol levels in myoblasts induce changes in proliferation and differentiation, which involves activation of Wnt/beta-catenin signaling pathway. In this study we used methyl-?-cyclodextrin (MbCD) to extract cholesterol from the membrane of chick skeletal muscle cells grown in culture. Using Ion Torrent-based sequencing, we compared the transcriptome of untreated and MbCD treated cells. Our aim was to define the genes that are expressed in these two conditions and relate their expression to cellular functions. RESULTS: Over 5.7 million sequences were obtained, representing 671.38 Mb of information. mRNA transcriptome profiling of myogenic cells after cholesterol depletion revealed alterations in transcripts involved in the regulation of apoptosis, focal adhesion, phagosome, tight junction, cell cycle, lysosome, adherens junctions, gap junctions, p53 signaling pathway, endocytosis, autophagy and actin cytoskeleton. Lim domain only protein 7 mRNA was found to be the highest up-regulated feature after cholesterol depletion. CONCLUSIONS: This is the first study on the effects of membrane cholesterol depletion in mRNA expression in myogenic cells. Our data shows that alterations in the availability of plasma membrane cholesterol lead to transcriptional changes in myogenic cells. The knowledge of the genes involved in the cellular response to cholesterol depletion could contribute to our understanding of skeletal muscle differentiation.
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