Exercise-Induced Skeletal Muscle Exosomes Promote Adipocyte Lipolysis

A higher level of total daily physical activity is associated with a reduced risk of Alzheimer¡¦s disease (AD), whereas low physical activity is associated with a higher risk for dementia in older individuals. In particular, exercise is associated with reduced risk for AD by decreasing amyloid load and increasing cognitive function, cerebral blood flow and brain volume. In contrast, obesity, and its related comorbidities, are risk factors for the development of AD and accelerate the decline of cognitive function. Preclinical studies have shown that dietinduced obesity significantly impairs short memory in AD mice. The mechanisms underlying the beneficial effects of physical activity on brain structure and cognitive function remains relatively unknown; further, how obesity might diminish the benefits of exercise has not been investigated. We have obtained preliminary data showing that transthyretin (Ttr) gene expression is significantly higher in the hippocampus of mice following eight weeks of running whereas in obese mice, Ttr expression is lower. This is an intriguing finding given that Ttr has been shown to have an important role in the clearing of beta-amyloid (AƒÒ) plaques. Further, we also found the hippocampal expression of three microRNAs, miR-129, -131 and -139, which are predicted to target Ttr, is lower in mice following exercise training compared to sedentary control mice but their expression is higher in the hippocampus of obese mice relative to lean mice. Based on these preliminary data, we hypothesize exercise slows the progression of AD by increasing hippocampal Ttr expression via downregulation of microRNA (miR-129, -131 and/or -139) expression. We further hypothesize that obesity will blunt the benefits of exercise by increasing the expression of one or more of these microRNAs thereby repressing Ttr expression. To test this hypothesis, we have established a collaboration with an expert in AD and brain imaging, Dr. Ai-Ling Lin. To test these hypotheses, we will pursue the following aims: Aim 1: Female, lean and obese AD(3xTg-AD) and control (B6129SP2/J) mice will undergo eight weeks of voluntary wheel running (or sedentary control) followed by cognitive and functional tests as well MRI testing to assess changes in brain vasculature, metabolism and structure; Aim 2: hippocampal and exosome microRNA (miR-129, -131 and -139) and Ttr gene expression will be determined by pPCR in the aforementioned groups. The parent R01 is focused on understanding how exercise-induced release of exosomal miR-1 increases the catecholamine sensitivity of adipocytes through upregulation of adrenergic signaling. The purpose of this supplement is to extend our analyses to mechanisms underlying the benefits of physical activity on the AD brain. If the results of the proposed studies support our hypothesis, a future R01 grant application will seek to more rigorously test our hypothesis through loss- and gain-of-function exosome and miRNA studies as well as identify miRNA target genes to define the pathways in the brain that may be responsive to exercise. More broadly, this new collaboration will enable us to combine analyses of brain, cognition, muscle and physical function in a variety of genetic mouse models to begin to understand the interplay between cognitive and physical functional decline with aging, and potential targets to delay, prevent or even reverse those processes.