Exercise-induced Skeletal Muscle Exosomes Promote Adipocyte Lipolysis

Exosomes are small extracellular vesicles that have emerged over the past few years as novel mediators of intercellular communication. We recently reported that exosomes released from activated satellite cells regulate extracellular matrix remodeling during skeletal muscle hypertrophy through the transport of the skeletal muscle-specific microRNA-206 (miR-206) to fibroblasts. The discovery of this novel role for satellite cells inspired us to further explore if exosomes are released from skeletal muscle cells in response to exercise and, if so, their impact on target tissue. Based on preliminary data, we hypothesize the enhanced adrenergic signaling in adipose tissue known to occur with exercise is mediated in part by muscle-specific miR-1 activation of ß3-adrenergic receptor (ß3-AR) expression. In particular, we have developed a working model in which: 1) exercise causes 2) skeletal muscle to release exosomes containing muscle-specific miR-1 that 3) transport miR-1 to adipocytes causing 4) CAATT/enhancer binding protein alpha (C/EBPa) activation of ß3-AR gene expression through miR-1-mediated repression of AP-2 thereby 5) enhancing catecholamine sensitivity of adipocytes 6) promoting the release of fatty acids and glycerol into the circulation as the result of increased lipolysis. The purpose of this proposal is to test this hypothesis by pursuing the following aims in both mice and humans: Aim 1: Determine the mechanism of action of exercise-induced exosomal miR-1 on adipocyte ß3-AR expression and quantify downstream effects on adipocyte adrenergic signaling and lipolysis; Specific Aim 2: Determine if skeletal muscle fiber-derived exosomes directly promote adipocyte lipolysis through enhanced ß-adrenergic signaling; Specific Aim 3: Determine if an acute bout of resistance exercise in humans promotes miR-1-mediated adipocyte lipolysis. There is great interest in determining what role skeletal muscle-derived exosomes have in the health benefits known to occur with exercise. A better understanding of the role of exosomes in the systemic adaptations that occur in response to exercise will provide the fundamental knowledge to use exosomes as a platform for the delivery of exercise mimetics. To the best of our knowledge, our preliminary data provides the first evidence that muscle-derived exosomes released in response to exercise is responsible for mediating the beneficial effect of exercise on adipose tissue metabolism.