Grant: Discovery Grants Program - Individual

The long term objective of the current proposal is to further investigate the role of changes in muscle cell fluid levels on the control of muscle metabolism, as we have previously shown that changes in muscle cell fluid levels lead to changes in how these cells metabolize energy. We will achieve a number of specific short term goals with this proposal; firstly, we will establish a detailed time course for changes in muscle cell fluid levels in response to changes in the composition of the fluid in which they are bathed. We will also determine the time course for recovery from such changes. Another goal of this work is to establish what intracellular signaling pathways are influenced by these changes in fluid volume and to determine the extent to which these pathways are altered. Finally, we will establish how the changes in these intracellular signaling pathways influence metabolism within skeletal muscle. During previous experiments, we established a working model that allows us to successfully alter the fluid volume of single isolated skeletal muscles. We also have shown that during rest and after muscle contraction that energy metabolism is altered with differing fluid levels within the muscle. It is proposed that changes in muscle cell volume contribute as a control mechanism to the changes in substrate metabolism that occur within skeletal muscle. The proposed experiments are designed to better understand the influence of these fluid level changes on energy use in muscle. They are also intended to allow us to better understand the signaling processes used in muscle during fluid changes, and to determine if these signaling changes are resulting in the changes we are seeing in energy metabolism in the muscle. Collectively, this work will allow for a better understanding of how skeletal muscle uses energy and the factors that can influence these functions. Understanding the mechanisms behind these processes has implications in various pathological conditions of fuel homeostasis such as obesity and type 2 diabetes.