Adipose-Specific Metabolic Effects of Exercise-Induced Skeletal Muscle Exosomes

Exosomes are small extracellular vesicles that contain miRNAs and have emerged over the past few years as novel mediators of intercellular communication. We and others have reported that adipose tissue miRNAs differ in insulin resistant versus insulin sensitive subjects. More specifically, we observed increased miR-1 in the subcutaneous adipose tissue of insulin sensitive subjects. Since miR-1 is a muscle-specific miRNA, we were inspired us to explore whether exosomes are released from muscle cells in response to resistance exercise and targeted to adipose tissue. Our preliminary data indicate that resistance exercise induces the release of muscle-derived exosomes, containing miR-1, that are absorbed by adipose tissue and drive transcription of â-adrenergic and pro-lipolytic genes. Our preliminary data further indicate that resistance exercise enhances adipocyte lipolysis in response to isoproterenol. This proposal expands upon our preliminary data, and is based on the overarching hypothesis that resistance exercise improves adipose tissue metabolic function via miR-1-containing musclederived exosomes. More specifically, I hypothesize that miR-1 up-regulates adipose CEBPá, which in turn up-regulates PPARã and its transcriptional targets, leading to whole-body metabolic benefits. The purpose of this proposal is to test this working hypothesis by pursuing the following aims in mice: Aim 1: To compare exosomal release following muscle hypertrophy in lean versus diet-induced obese mice. Aim 2: To determine whether muscle hypertrophy reverses the metabolic consequences of high fat feeding in an exosome dependent manner. Aim 3: Determine whether muscle hypertrophy up-regulates adipose CEBPá and PPARã in an exosome-dependent manner. Our preliminary data indicate that resistance exercise-induced exosomes mediate the beneficial effects 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 regarding how resistance exercise ameliorates metabolic deficits associated with obesity and prediabetes