Exosomes participate in the alteration of muscle homeostasis during lipid-induced insulin resistance in mice
Open accessAbstract
AIMS/HYPOTHESIS: Exosomes released from cells can transfer both functional proteins and RNAs between cells. In this study we tested the hypothesis that muscle cells might transmit specific signals during lipid-induced insulin resistance through the exosomal route. METHODS: Exosomes were collected from quadriceps muscles of C57Bl/6 mice fed for 16 weeks with either a standard chow diet (SD) or an SD enriched with 20% palm oil (HP) and from C2C12 cells exposed to 0.5 mmol/l palmitate (EXO-Post Palm), oleate (EXO-Post Oleate) or BSA (EXO-Post BSA). RESULTS: HP-fed mice were obese and insulin resistant and had altered insulin-induced Akt phosphorylation in skeletal muscle (SkM). They also had reduced expression of Myod1 and Myog and increased levels of Ccnd1 mRNA, indicating that palm oil had a deep impact on SkM homeostasis in addition to insulin resistance. HP-fed mouse SkM secreted more exosomes than SD-fed mouse SkM. This was reproduced in-vitro using C2C12 cells pre-treated with palmitate, the most abundant saturated fatty acid of palm oil. Exosomes from HP-fed mice, EXO-Post Palm and EXO-Post Oleate induced myoblast proliferation and modified the expressions of genes involved in the cell cycle and muscle differentiation but did not alter insulin-induced Akt phosphorylation. Lipidomic analyses showed that exosomes from palmitate-treated cells were enriched in palmitate, indicating that exosomes likely transfer the deleterious effect of palm oil between muscle cells by transferring lipids. Muscle exosomes were incorporated into various tissues in vivo, including the pancreas and liver, suggesting that SkM could transfer specific signals through the exosomal route to key metabolic tissues. CONCLUSIONS/INTERPRETATION: Exosomes act as 'paracrine-like' signals and modify muscle homeostasis during high-fat diets.
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ELVs released from C2C12 myotubes treated with palmitate were enriched in palmitate compared to BSA-treated cells.
“Interestingly, ELVs released from C2C12 myotubes treated with palmitate were enriched in palmitate compared to BSA-treated cells (Aswad et al., 2014).”
From Skeletal Muscle-Released Extracellular Vesicles: State of the Art (2019) · cites this paper as Aswad et al., 2014
ELV-MT are enriched in palmitic acid, stearic acid, oleic acid, palmitoleic acid, and lauric acid compared to other fatty acids.
“As shown on Figure 5D, ELV-MT are enriched in palmitic acid, stearic acid, oleic acid, palmitoleic acid, and lauric acid compared to others FA (Aswad et al., 2014).”
From Skeletal Muscle-Released Extracellular Vesicles: State of the Art (2019) · cites this paper as Aswad et al., 2014
Muscle differentiation markers (myogenin, MyoD1, and CKMT2) are down-regulated in recipient myotubes after transfer of palmitate contained in ELV-MT from DIO mice.
“muscle differentiation markers (myogenin, MyoD1, and CKMT2) were down-regulated”
From Skeletal Muscle-Released Extracellular Vesicles: State of the Art (2019) · cites this paper as Aswad et al., 2014
Palmitate contained in ELV-MT from DIO mice is transferred in recipient myotubes and results in up-regulation of 240 genes involved in cell cycle and cellular adhesion.
“palmitate contained in ELV-MT from DIO mice was transferred in recipient myotubes and resulted in the up-regulation of 240 genes involved in cell cycle and cellular adhesion.”
From Skeletal Muscle-Released Extracellular Vesicles: State of the Art (2019) · cites this paper as Aswad et al., 2014
ELV-MT enriched in palmitate affects muscle phenotype.
“showing that ELV-MT enriched in palmitate affected muscle phenotype.”
From Skeletal Muscle-Released Extracellular Vesicles: State of the Art (2019) · cites this paper as Aswad et al., 2014
Intraperitoneal injections of fluorescent SkM-ELVs result in fluorescent labeling of 9 organs in mice.
“Intraperitoneal injections of fluorescent SkM-ELVs resulted in the fluorescent labeling of 9 organs in mice”
From Skeletal Muscle-Released Extracellular Vesicles: State of the Art (2019) · cites this paper as Aswad et al., 2014
IL-6 and cyclin D1 are strongly upregulated, whereas Glut4 is downregulated, in recipient myotubes after transfer of palmitate contained in ELV-MT from DIO mice.
“the pro-inflammatory cytokine IL-6 and the cell cycle regulator cyclin D1 were strongly upregulated, whereas Glut4 involved in glucose uptake was downregulated.”
From Skeletal Muscle-Released Extracellular Vesicles: State of the Art (2019) · cites this paper as Aswad et al., 2014
Mice fed with a palmitate-enriched diet release more ELV-MT.
“mice fed with a palmitate-enriched diet released more ELV-MT”
From Skeletal Muscle-Released Extracellular Vesicles: State of the Art (2019) · cites this paper as Aswad et al., 2014
Palmitate-induced SkM insulin-resistance triggers the release of a new population of ELV-MT enriched in palmitate in DIO mice compared to NCD mice.
“palmitate-induced SkM insulin-resistance triggered the release of a new population of ELV-MT enriched in palmitate, in diet-induced obese mice (DIO) compared normal chow diet mice (NCD)”
From Skeletal Muscle-Released Extracellular Vesicles: State of the Art (2019) · cites this paper as Aswad et al., 2014
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- Authors
- Aswad, H., Forterre, A., Wiklander, O. P. B., Vial, G., Danty-Berger, E., Jalabert, A., Lamazière, A., Meugnier, E., Pesenti, S., Ott, C., Chikh, K., El-Andaloussi, S., Vidal, H., Lefai, E., Rieusset, J., & Rome, S.
- Affiliations
- Inserm (FR)
- Karolinska University Hospital (SE)
- Centre National de la Recherche Scientifique (FR)
- Hospices Civils de Lyon (FR)
- Corresponding author
- Rome, Sophie
- ORCID
- Venue
- Diabetologia
- Published
- 2014-07-30
- Volume
- 57
- Issue
- 10
- Pages
- 2155-2164
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- PMC
- PMC4153976
- OpenAlex
- W1969387165
- Cited by
- 185
- References
- 41
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 23 · 2023: 24 · 2022: 23 · 2021: 23 · 2020: 18 · 2019: 17 · 2018: 10 · 2017: 14 · 2016: 7 · 2015: 4
- FWCI
- 3.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Diabetologia (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by)
- HAL (submittedVersion)
- Funders
- Fondation pour la Recherche Médicale (FRM-2010)
- Institut National de la Recherche Agronomique
- Université de Lyon
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- exosomes, lipid-induced insulin resistance, skeletal muscle homeostasis, palmitate, palm oil, high-fat diet, myoblast proliferation, myogenesis, Akt phosphorylation, paracrine signaling, obesity, cell cycle genes
- MeSH terms
- Animals, Cell Line, Homeostasis, Insulin Resistance, Male, Mice, Inbred C57BL, Palmitates, Blotting, Western, Muscle, Skeletal, Oleic Acid, Mice, Exosomes, Real-Time Polymerase Chain Reaction
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