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Mechanical overload-induced muscle-derived extracellular vesicles promote adipose tissue lipolysis

ABSTRACT: How regular physical activity is able to improve health remains poorly understood, but release of substances from skeletal muscle following exercise is one proposed mechanism. Here we describe a novel mechanism through which physical activity initiates extracellular vesicle (EV)-mediated communication between skeletal muscle and adipose tissue causing increased adipocyte lipolysis as a result of enhanced catecholamine sensitivity. In response to a hypertrophic stimulus induced by mechanical overload (MOV), skeletal muscle released EVs containing muscle-specific miR-1 which were preferentially taken up by epididymal white adipose tissue (eWAT) and were associated with elevated adrenergic signaling and lipolysis. Inhibiting EV release by GW4869 treatment prevented the MOV-induced increase in eWAT miR-1 abundance and expression of lipolytic factors. miR-1 was shown to induce adrenergic receptor beta β3 (Adrβ3) expression in adipocytes by targeting transcription factor AP-2, alpha (Tfap2α, a known repressor of Adrβ3 expression. Ex vivo experiments showed enhanced catecholamine sensitivity and elevated fatty acid oxidation in eWAT following MOV. Following a bout of resistance exercise in humans, skeletal muscle miR-1 expression was decreased with a concomitant increase in EV miR-1 abundance, suggesting that a skeletal muscle-adipose tissue axis is operative in humans. Altogether, our highly novel findings demonstrate that skeletal muscle promotes metabolic adaptations in adipose tissue in response to MOV via EV-mediated delivery of miR-1.

ORGANISM(S): Mus musculus

PROVIDER: GSE150162 | GEO | 2021/05/26

REPOSITORIES: GEO

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Project description:The Finland-United States Investigation of NIDDM Genetics (FUSION) study is a long-term effort to identify genetic variants that predispose to type 2 diabetes (T2D) or that impact the variability of T2D-related quantitative traits (QTs). Skeletal muscle and adipose are major insulin target tissues and play key roles in insulin resistance. We hypothesize that a subset of T2D and related QT variants alter gene expression in skeletal muscle and adipose tissue. For this FUSION Tissue Biopsy Study, we have obtained and are analyzing RNA-Seq, microRNA (miRNA)-Seq, and DNA methylation (methyl)-Seq data on biopsy samples from 331 individuals from across the range of glucose tolerance: 124 normal glucose tolerance (NGT), 77 impaired glucose tolerance (IGT), 44 impaired fasting glucose (IFG), and 86 newly-diagnosed T2Ds. Participants completed two study visits, two weeks apart. First visits comprised most of the clinical phenotyping, including four-point OGTT (fasting, and 30, 60, and 120 minute post-load); BMI, WHR; lipids; blood pressure; and many other variables. Participants also completed FUSION health history, medication, and lifestyle questionnaires. At second visit, we obtained ~250mg vastus lateralis skeletal muscle, ~750mg abdominal subcutaneous adipose, and a ~5x15mm section of abdominal skin. Visits were completed in March 2013. RNA isolation is ongoing in the Collins laboratory at the NIH, RNA and miRNA sequencing at the NIH Intramural Sequencing Center (NISC), and genotyping at the Center for Inherited Disease Research (CIDR). Individual-level data is available here for the 306 individuals who consented to data deposit. To focus on evaluation of gene expression and its regulation in skeletal muscle, we analyzed mRNA extracted from vastus lateralis skeletal muscle obtained from 271 of the 331 individual subjects from Finland, along with genome-wide genotypes. Individual-level data is available here for the 250 subjects who reconsented to the use of their data. Release phs001048.v2.p1 adds muscle data for an additional 42 subjects and data from adipose tissue for 276 subjects. Total RNA was isolated using Trizol extraction in the Collins laboratory at the NIH. The mRNA was poly-A selected, 24-plex libraries were generated using the Illumina TruSeq directional mRNA-seq library protocol and RNA sequencing was performed on HiSeq2000 sequencers using 101bp paired-end reads at NISC. miRNA libraries were prepared from total RNA from 296 muscle and 270 adipose samples, pooled and sequenced 50bp single-end reads on Illumina HiSeq2500. Data for 272 muscle and 251 adipose samples are available here for individuals with consent for data deposit. DNA was extracted from blood in the Collins laboratory, and genotyping on the Illumina Omni2.5M array was performed at CIDR. Genotypes were imputed using the HRC 2016 reference panel. In order to assess regions of open chromatin in skeletal muscle, we obtained muscle tissue from a commercial provider to perform ATAC-seq; these samples were sequenced at the University of Michigan DNA Sequencing Core. Greater than 90% of the approximately 80 loci associated with T2D and the 100s of loci associated with T2D-related traits (glucose and insulin, anthropometrics, lipids) through genome-wide association studies occur in non-coding regions, suggesting a strong regulatory component to disease susceptibility. Regulatory element activity is often tissue-specific, which further complicates discovery of the causal/functional variation. Therefore, there is a critical need to understand the full spectrum of genetic variation and regulatory element usage in T2D-relevant tissues. To that end, this study contains whole genome sequence and whole genome bisulfite sequence, and/or Illumina MethylationEPIC Array data, of two tissues relevant to T2D: skeletal muscle and adipose tissue from individuals with glucose tolerance categories ranging from normal to T2D, providing a comprehensive survey of both individual genetic variation as well as DNA methylation across different tissues from multiple individuals.

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Mechanical overload-induced muscle-derived extracellular vesicles promote adipose tissue lipolysis

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