Understanding the Importance of the Melanocortin 3 Receptor in Muscle Mass Accrual and Body Composition

We are yet to understand how the body regulates muscle mass in response to nutrient sensing at a whole organism level. The loss of muscle mass occurs in a range of diseases, including cancer cachexia, in which mortality risk is substantially increased by muscle wasting. The melanocortin signalling system in the hypothalamus is a crucial node in energy and nutrient sensing, with growing evidence implicating the understudied melanocortin 3 receptor (MC3R) in the control of body composition and lean mass. To date, the influence of MC3R tone on muscle mass has only been studied in mice and humans lacking MC3R from conception. To understand MC3R action and the spatial and temporal relevance of the receptor in regulating muscle mass, using in vivo and ex vivo approaches, IMMAc will:7.Determine the neuroendocrine effects of MC3R activity8.Assess the role of a putatively critical MC3R sub-population in controlling body composition and muscle mass9.Determine the importance of MC3R for muscle mass in a mature organism and the extent to which MC3R tone can be manipulated to therapeutically alter muscle mass in adulthoodNeuroendocrine impacts of MC3R activation will be examined using ex vivo hypothalamic culture and in vivo. Neuron-specific deletion of MC3R will allow mechanistic understanding of MC3R action, and the physiological and functional consequences of MC3R activation on skeletal muscle will be assessed by examining physical activity and fibre functionality.IMMAc will provide understanding of mechanisms underlying control of muscle mass and body composition by a key central nervous system receptor. Moreover, this project will reveal the relevance of MC3R for muscle mass in adult life and explore the therapeutic potential of manipulating MC3R to address the global health challenges of muscle atrophy and obesity by increasing lean mass in cachexia and improving increasingly prevalent anti-obesity agents through preventing loss of functional muscle.