Glucose metabolism & skeletal muscle growth

About This Grant

PROJECT SUMMARY The maintenance of skeletal muscle mass is not only required for activities of daily living, but it is critical for the prevention of metabolic diseases such as type 2 diabetes. Resistance training and the mechanical loading of skeletal muscle are known to stimulate muscle hypertrophy and glucose metabolism; yet the molecular basis underlying the ability of mechanical loading to stimulate these processes is still not well understood. The long- term goal of this research is to develop novel therapies that mimic the beneficial effects of mechanical loading on muscle size and glucometabolic health. Our overall hypothesis is that mechanical loading stimulates muscle glucose uptake via a currently unknown glucose transport mechanism to not only fuel the energetic and biosynthetic demands of muscle hypertrophy, but also to direct the transcriptional response to loading. The rationale for this work is based on studies in which genetic deletion of the two main glucose transporters found in skeletal muscle did not impair mechanical load-stimulated muscle glucose uptake. It is also based on studies in which mechanical loading stimulated glucometabolic flux and preserved hypertrophic growth in high fat diet- induced insulin resistant skeletal muscles. To test the overall hypothesis, the following specific aims were proposed: 1) Identify the glucose transporter(s) activated by mechanical loading in skeletal muscle; 2) Determine if glucose uptake is necessary for mechanical load-stimulated muscle hypertrophy; and 3) Determine if enhanced muscle glucometabolic flux is necessary for the transcriptional response to mechanical loading. The first aim will involve incubating mechanical load-stimulated muscles in a glucose photoaffinity reagent to capture active cell surface-localized GLUTs and then determining their identity using mass spectrometry-based analyses. The second and third aims will involve administering mice with a new small molecule GLUT inhibitor to block mechanical load-stimulated glucose uptake in vivo. The second aim will focus on examining the inhibitor effects on muscle size and protein synthesis, whereas the third aim will focus on examining the inhibitor effects on the metabolic and transcriptional responses to loading. The proposed research is innovative because it focuses on the use of unbiased molecular, biochemical, and physiological approaches to not only identify the GLUT(s) responsible for mechanical load-stimulated muscle glucose uptake, but to provide novel mechanistic insight into the relationship between glucometabolic flux and the transcriptional alterations needed for muscle hypertrophy. The proposed research is significant because it will identify novel genes and proteins that are part of the molecular mechanism by which mechanical loading stimulates myofiber hypertrophy and glucometabolic flux. This is a key first step towards the generation of therapies aimed at increasing muscle size and improving muscle metabolic health for the treatment of individuals with chronic muscle wasting or glucometabolic diseases.