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

Abstract

How regular physical activity is able to improve health remains poorly understood.The release of factors from skeletal muscle following exercise has been proposed as a possible mechanism mediating such systemic benefits. We describe a mechanism wherein skeletal muscle, in response to a hypertrophic stimulus induced by mechanical overload (MOV), released extracellular vesicles (EVs) containing musclespecific miR-1 that were preferentially taken up by epidydimal white adipose tissue (eWAT). In eWAT, miR-1 promoted adrenergic signaling and lipolysis by targeting Tfap2α, a known repressor of Adrβ3 expression. Inhibiting EV release prevented the MOV-induced increase in eWAT miR-1 abundance and expression of lipolytic genes. Resistance exercise decreased skeletal muscle miR-1 expression with a concomitant increase in plasma EV miR-1 abundance, suggesting a similar mechanism may be operative in humans. Altogether, these findings demonstrate that skeletal muscle promotes metabolic adaptations in adipose tissue in response to MOV via EV-mediated delivery of miR-1.

Skeletal Muscle Cell Growth Alters the Lipid Composition of Extracellular Vesicles

“…Conceptually, this would ensure that muscle consumes the appropriate amount of energy required for anabolism. Furthermore, this idea is in agreement with our previous work, where we show that EVs secreted by skeletal muscle during mechanical overload target adipose tissue, resulting in an increase in lipolysis [22]. This could be a mechanism whereby growing skeletal muscle signals to adipose tissue to increase the triacylglycerides that would support hypertrophic growth.…”

“…Previously, it was found that Cer plays a role in EV biogenesis by interacting with endosomes and lysosomes, initiating an ESCRTindependent pathway [32,75] via nSMase2, which is essential for exosome biogenesis in some cells [76]. We previously found that mice treated with an nSmase2 inhibitor (GW4869) had a significant decrease in EV concentration [22]. Cer is also important for mediating the EV response in the recipient cell, which suggests that this particular lipid adds to the functionality of EVs.…”

“…A major focus in EV research has been identifying the miRNA content carried within EVs (ex-omiRs) [9,17,18]. Several studies have demonstrated that exomiRs are delivered to other cells, where they regulate their cognate target genes usually at the posttranscriptional level [19][20][21][22]. While these studies clearly demonstrated the functional transfer of miRNA, some studies have suggested that the modulation of gene expression in target cells via ex-omiRs may not account for all the biological properties of EVs [23].…”

“…As noted previously, lipids may play a fundamental role in EV biology; however, data regarding lipids in skeletal muscle-derived EVs is lacking. We recently published data showing that skeletal muscle-derived EVs are secreted during muscle hypertrophy which subsequently target adipose tissue, resulting in an increase in lipolysis [22]. This is not seen under resting conditions, suggesting that during skeletal muscle hypertrophy, a subset of EVs is secreted, influencing the biological function of the recipient cell.…”

Exercise Training and Circulating Small Extracellular Vesicles: Appraisal of Methodological Approaches and Current Knowledge

“…Currently several studies have investigated elements of the response of circulating small EVs to acute aerobic (Frühbeis et al, 2015;Guescini et al, 2015;Bertoldi et al, 2018;D'Souza et al, 2018;Lovett et al, 2018;Oliveira et al, 2018;Whitham et al, 2018;Brahmer et al, 2019;Yin et al, 2019;Karvinen et al, 2020;Rigamonti et al, 2020;Gao et al, 2021;Neuberger et al, 2021;Zhang et al, 2021), resistance (Annibalini et al, 2019;Just et al, 2020;Vechetti et al, 2021) or combined plyometric and downhill running (Lovett et al, 2018) exercise. Most of these studies have attempted to characterize circulating small EVs separated from plasma (Frühbeis et al, 2015;Guescini et al, 2015;D'Souza et al, 2018;Lovett et al, 2018;Whitham et al, 2018;Annibalini et al, 2019;Brahmer et al, 2019;Yin et al, 2019;Just et al, 2020;Rigamonti et al, 2020;Gao et al, 2021;Neuberger et al, 2021;Vechetti et al, 2021), although four studies have separated small EVs from serum (Bertoldi et al, 2018;Oliveira et al, 2018;Karvinen et al, 2020;Zhang et al, 2021).…”