Skeletal Muscle-Released Extracellular Vesicles: State of the Art

Sophie Rome, Alexis Forterre, Maria Luisa Mizgier, Karim Bouzakri, Sophie Rome, Alexis Forterre, Maria Luisa Mizgier, Karim Bouzakri

Abstract

All cells export part of their intracellular content into the extracellular space through the release of various types of extracellular vesicles (EVs). They are synthetized either from the budding of the plasma membrane [i.e., microparticles (MPs, 150-300 nm size)] or from the late endosomes in which intraluminal vesicles progressively (ILVs) accumulate during their maturation into multivesicular bodies (MVBs). ILVs are then released into the extracellular space through MVB fusion with the plasma membrane [i.e., exosomes (50-100 nm size)]. In the context of metabolic diseases, recent data have highlighted the role of EVs in inflammation associated with pancreas dysfunction, adipose tissue homeostasis, liver steatosis, inflammation, and skeletal muscle (SkM) insulin resistance (IR). Among these insulin-sensitive tissues, SkM is the largest organ in human and is responsible for whole-body glucose disposal and locomotion. Therefore, understanding the contribution of SkM-EVs in the development of diabetes/obesity/dystrophy/,-related diseases is a hot topic. In this review, we have summarized the role of SkM-EVs in muscle physiology and in the development of metabolic diseases and identify important gaps that have to be filled in order to have more precise information on SkM-EVs biological actions and to understand the functions of the different subpopulations of SkM-EVs on the whole-body homeostasis.

Keywords: exosomes; extracellular vesicles; microparticles; organ cross-talks; skeletal muscle (myotubes).

Figures

Figure 1
Figure 1
Representation of muscle-release extracellular vesicles (EVs). (A) Exosomes are formed in late endosomes called multivesicular endosomes (MVBs), containing internal vesicles (ILVs) that pack and store molecules in membrane-bound structures. Endosomes are an intermediate compartment between the plasma membrane where endocytosis takes place and lysosomes where these molecules are degraded. MVB biogenesis can occur with the ESCRT machinery (ESCRT+) or without (ESCRT−) (Hessvik and Llorente, 2018). MVBs rich in lysobisphosphatidic acid (LBPA) but low in cholesterol migrate toward lysosomes and fuse with them. Those rich in cholesterol but low in LBPA migrate to the plasma membrane to fuse and release their ILVs as exosomes (Laulagnier et al., 2005; Colombo et al., 2014). (B) Electron microscopy showing the release of apoptotic bodies from an apoptotic C2C12 myoblast (personal data from S. Rome) (scale = 1 μm). (C) Microparticles (MPs) represent a heterogeneous population of small plasma membrane vesicles (Morel et al., 2011). Electron microscopy of human myotubes showing the release of MPs from the plasma membrane (scale = 1 μm) (personal data from S. Rome). (D) Due to their small size exosome-like vesicles (ELVs) can be visualized only through electron microscopy. ELVs released from quadriceps explants labeled with anti-CD81 gold particles (personal data from S. Rome).
Figure 2
Figure 2
Currently used protocols to purify ELVs from skeletal muscle (SkM) cells conditioned medium, SkM explants, or myofibers. The origin/composition and the level of purity of the EV pellets from steps 1–3 have to be validated according the MISEV2018 guidelines (Thery et al., 2018).
Figure 3
Figure 3
Summary of all vesicles identified in the conditioned-medium from skeletal muscle (SkM) cells based on the detection of specific subsets of tetraspanins by proteomics or Western-blot.
Figure 4
Figure 4
(A) Proteomic analyses identified specific subsets of proteins in MPs and ELVs released from differentiated human SKM cells [full list of proteins are in Le Bihan et al. (2012)], protein are identified from protein fragments). (B) Significant GO biological functions enriched in genes commonly identified C2C12 myotubes- and primary human myotubes-ELVs isolated from conditioned medium. Proteomic data are from Forterre et al. (2014a) and Le Bihan et al. (2012) and were analyzed with PANTHER version 11 (Mi et al., 2017).
Figure 5
Figure 5
(A) Overlap between the number of proteins from C2C12 ELV-MB and ELV-MT (see Forterre et al., 2014a for a full list of proteins, proteins are identified from protein fragments). (B) Overlap between three independent protomic analyses from C2C12 ELV-MB. (C) Left: overlap between the protein content of ELV-MB and the secretome from C2C12 myoblasts (Forterre et al., 2014a); right: overlap between the protein contents of ELV-MT and the secretome from human differentiated MT (Le Bihan et al., 2012). Only significant GO functions between the two sets of proteins are indicated. (D) Fatty acid composition of ELV-MT from C2C12 (Aswad et al., 2014).
Figure 6
Figure 6
(A–C) were built from the sequencing data published in Sork et al. (2018). (A) Percentage of small and large RNAs in C2C12 myoblasts and their released ELV-MB. (B) Number small RNA species in C2C12 myoblasts vs. ELV-MB expressed as percentages. (C) Functional enrichment analyses of the predicted target genes from ELV-MB miRNAs. Target predictions and the identification of significant biological pathways were performed with DIANA-microT-CDS and mirPath v.3 (http://snf-515788.vm.okeanos.grnet.gr). (D) Overlap between the miRNA species found in muscle cells and their respective ELVs (n = 3). The same quantity of total RNA was used as starting material for qRT-PCR (Forterre et al., 2014b).
Figure 7
Figure 7
Summary of the roles of exosome-like vesicles released from skeletal muscle (SkM) cells, published so far.

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