The role of extracellular vesicles in skeletal muscle and systematic adaptation to exercise

Abstract

Regular exercise has a central role in human health by reducing the risk of type 2 diabetes, obesity, stroke and cancer. How exercise is able to promote such systemic benefits has remained somewhat of a mystery but has been thought to be in part mediated by the release of myokines, skeletal muscle-specific cytokines, in response to exercise. Recent studies have revealed skeletal muscle can also release extracellular vesicles (EVs) into circulation following a bout of exercise. EVs are small membrane-bound vesicles capable of delivering biomolecules to recipient cells and subsequently altering their metabolism. The notion that EVs may have a role in both skeletal muscle and systemic adaptation to exercise has generated a great deal of excitement within a number of different fields including exercise physiology, neuroscience and metabolism. The purpose of this review is to provide an introduction to EV biology and what is currently known about skeletal muscle EVs and their potential role in the response of muscle and other tissues to exercise.

Keywords: exercise; extracellular vesicles; microRNAs; skeletal muscle.

Figure 1.. Schematic representation of extracellular vesicle subtypes: exosomes, microvesicles and apoptotic bodies

Illustration showing the release of extracellular vesicle subtypes, namely exosomes, microvesicles and apoptotic bodies through various mechanisms mainly outward budding and exocytosis.

Figure 2.. Pathways involved in extracellular vesicle biogenesis

In the classical pathway, extracellular proteins can be internalized to form early endosomes. Invagination of the early endosome are responsible for the origin of the intraluminal vesicles (ILV)/multivesicular body (MVB). The MVB can fuse directly to the plasma membrane releasing its content, exosomes, or fuse with the lysosomes and have its content degraded. Another mechanism of exosomes biogenesis is direct outward budding of the plasma membrane. Microvesicle biogenesis occurs by the generation of small cytoplasmic protrusions that cause the cellular membrane to pinch off giving rise to microvesicles.

Figure 3.. Mechanism of EV uptake by recipient cell

After release, EVs can be taken up by the recipient cell through: (1) lipid rafts that facilitate endocytosis, (2) caveolin-mediated endocytosis, which involves invaginations of the plasma membrane resulting in EV internalization, (3) micropinocytosis, which occurs when the membrane forms ruffles that surround the extracellular space and engulf the incoming EV, leading to entry into the cell, and (4) phagocytosis of the EV or alternatively fusion of the EV directly to the plasma membrane.

Figure 4.. Gene pathway enrichment analysis of the predicted targets of the identified miRNAs found in EVs

The horizontal bars represent the number of genes in each pathway. The vertical bars represent the major biological pathways. RNAhybrid and Miranda programs were used to determine the predicted target genes of the published miRNAs isolated from exercise-induced EVs.