Skeletal Muscle-Derived Exosomal miR-146a-5p Inhibits Adipogenesis by Mediating Muscle-Fat Axis and Targeting GDF5-PPARγ Signaling

Abstract

Skeletal muscle-fat interaction is essential for maintaining organismal energy homeostasis and managing obesity by secreting cytokines and exosomes, but the role of the latter as a new mediator in inter-tissue communication remains unclear. Recently, we discovered that miR-146a-5p was mainly enriched in skeletal muscle-derived exosomes (SKM-Exos), 50-fold higher than in fat exosomes. Here, we investigated the role of skeletal muscle-derived exosomes regulating lipid metabolism in adipose tissue by delivering miR-146a-5p. The results showed that skeletal muscle cell-derived exosomes significantly inhibited the differentiation of preadipocytes and their adipogenesis. When the skeletal muscle-derived exosomes co-treated adipocytes with miR-146a-5p inhibitor, this inhibition was reversed. Additionally, skeletal muscle-specific knockout miR-146a-5p (mKO) mice significantly increased body weight gain and decreased oxidative metabolism. On the other hand, the internalization of this miRNA into the mKO mice by injecting skeletal muscle-derived exosomes from the Flox mice (Flox-Exos) resulted in significant phenotypic reversion, including down-regulation of genes and proteins involved in adipogenesis. Mechanistically, miR-146a-5p has also been demonstrated to function as a negative regulator of peroxisome proliferator-activated receptor γ (PPARγ) signaling by directly targeting growth and differentiation factor 5 (GDF5) gene to mediate adipogenesis and fatty acid absorption. Taken together, these data provide new insights into the role of miR-146a-5p as a novel myokine involved in the regulation of adipogenesis and obesity via mediating the skeletal muscle-fat signaling axis, which may serve as a target for the development of therapies against metabolic diseases, such as obesity.

Myalgic encephalomyelitis/chronic fatigue syndrome from current evidence to new diagnostic perspectives through skeletal muscle and metabolic disturbances

“…MiR‐146a‐5p was downregulated in plasma, 100 PBMC fraction, 99 and natural killer cells 101 of ME/CFS patients. Qin and colleague demonstrated the importance of miR‐146a‐5p in the communication of skeletal muscle with other tissues through exosomes 102 . Its down‐modulation in the plasma of ME/CFS patients may support the inability of skeletal muscle to correctly communicate with other tissues, which causes systemic alterations.…”

“…Qin and colleague demonstrated the importance of miR-146a-5p in the communication of skeletal muscle with other tissues through exosomes. 102 Its down-modulation in the plasma of ME/CFS patients may support the inability of skeletal muscle to correctly communicate with other tissues, which causes systemic alterations. According to two studies, miR-233 is downregulated in leukocytes from patients.…”

The role of extracellular vesicle-derived miRNAs in adipose tissue function and metabolic health

“…Promote β cell apoptosis and may contribute to type 1 diabetes development [29] Hepatocyte (early onset obesity) AT, skeletal muscle, and liver cells miR-3075 Fa2h Augments insulin signaling [30] Islet resident M1 macrophage (Obese mice) Pancreatic β cell miR-212-5p Sirt2 Inhibits insulin secretion [31] Pancreatic β cells (lean mice) Hepatocyte miR-26a Augments insulin sensitivity [32] Skeletal muscle Adipose tissue miR-146a-5p GD5F Inhibits adipogenesis [33] ATM, adipose tissue macrophages; BMDM, bone marrow-derived macrophages; EV, extracellular vesicle.…”

“…This function of hepatic EVs on insulin signaling is believed to occur as a result of miR-3075s action on recipient extrahepatic tissues such as adipose tissue and skeletal muscle [ 30 ] . In another study, Qin et al [ 33 ] show that miR-146a-5p is highly enriched in skeletal muscle-derived EVs. When these EVs are injected into recipient mice, exosomes, together with miR-146a, are readily taken up by various adipose tissue depots, where miR-146a-5p inhibits adipogenesis [ 33 ] .…”

“…In another study, Qin et al [ 33 ] show that miR-146a-5p is highly enriched in skeletal muscle-derived EVs. When these EVs are injected into recipient mice, exosomes, together with miR-146a, are readily taken up by various adipose tissue depots, where miR-146a-5p inhibits adipogenesis [ 33 ] . Similarly, Xu et al [ 32 ] report that miR-26a not only regulates insulin secretion by acting on pancreatic β-cells but also regulates insulin signaling in peripheral tissues such as the liver via EV-mediated transfer.…”