Summary 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 skeletal muscle stem cells regulate extracellular matrix remodeling during muscle hypertrophy through the transport of skeletal muscle-specific miR-206 to fibroblasts. The discovery of this novel role for muscle stem cells inspired us to further explore if exosomes are released from muscle cells in response to resistance exercise and, if so, their impact on target tissues. Based on preliminary data, we hypothesize that enhanced adrenergic signaling in adipose tissue in response to resistance exercise is mediated in part by exosomal muscle-specific miR-1 activation of β3-adrenergic receptor (β3-AR) expression. In particular, we have developed a working model in which exercise causes skeletal muscle cells to release exosomes containing muscle-specific miR-1 that transport miR-1 to adipocytes. As a result, CAATT/enhancer binding protein alpha (C/EBPα) activates β3-AR gene expression through miR-1-mediated repression of AP-2α, thereby enhancing catecholamine sensitivity of adipocytes and promoting the release of fatty acids and glycerol into the circulation as the result of increased lipolysis. The purpose of the proposed studies is to test our working model by pursuing the following aims in both mice and humans: Aim 1: Determine if exercise-induced exosomal miR-1 enhances adipocyte adrenergic signaling through activation of β3-AR expression; Aim 2: Determine if human skeletal muscle fiber-derived exosomes directly promote adipocyte lipolysis through enhanced β-adrenergic signaling; Aim 3: Determine if an acute bout of resistance exercise in humans promotes miR-1-mediated adipocyte lipolysis. Our preliminary data provide the first evidence demonstrating that resistance exercise-induced exosomes mediate the beneficial effect of exercise on adipose tissue metabolism. A better understanding of the role of exosomes in the systemic adaptations that occur in response to resistance exercise are expected to provide the fundamental knowledge necessary to use exosomes as a platform for the delivery of exercise mimetics to treat obesity.

NARRATIVE Obesity is known to exacerbate numerous diseases that represent urgent public health problems, including heart failure, coronary heart disease, type 2 diabetes, breast and colon cancer. The purpose of the proposed study is to investigate the mechanism through which resistance exercise causes skeletal muscle to communicate with adipose tissue to promote the burning of fat. The findings from this study are expected to provide the fundamental knowledge necessary to develop a novel therapeutic strategy to treat obesity using exosomal miR-1 delivery to adipose tissue.