Diabetes mellitus type 2 (T2D) is a disease that has become a worldwide epidemic. It is characterized by rising glucose levels because the body does not respond adequately to insulin anymore. Skeletal muscle is an important tissue for the development of T2D as it usually stores most of the glucose after we eat. Skeletal muscle is also efficient for the treatment of T2D when it is activated by exercise and physical activity. Our aim is to understand which signals direct a muscle cell to form a healthy muscle that fully responds to insulin. Significance of this work Previous studies on skeletal muscle in T2D have mostly focused on fully differentiated skeletal muscle, while we are investigating muscle cells before they form muscle fibers. This approach could help us to understand novel aspects of why T2D develops and might also give rise to new therapeutic strategies. The results of this project are not limited to T2D, but could be relevant to other muscle-related diseases as well. There have been little advances in clinical approaches to treat muscle injury or muscle wasting. The identification of cellular signals that suppress the normal direction from a muscle cell to a healthy muscle fiber would impact many research areas. Aging has also been associated with exhaustion of muscle cells over time and targeting adverse cell signals could permit to preserve autonomy and muscle strength in the elderly. Finally, the increased incidence of heart failure and chronic obstructive pulmonary disease places a high priority on public health. Numerous studies have linked abnormalities in skeletal muscle to early fatigue and exhaustion in these populations. Targeting cell signals that prevent muscle fiber formation could therefore also offer new strategies to decrease illness in these patients. Methods Adult skeletal muscle is continuously replaced by muscle cells that fuse to preexisting muscle fibers or build new ones. We are isolating these muscle cells from different animal models and also from patients with T2D. We then study in these muscle cells the levels of genes called microRNAs that have only been discovered about 10 years ago. MicroRNAs have already been shown to be important cell signals that control the levels of many proteins. Their role in muscle cells has not been analyzed in detail yet. After we have characterized which microRNAs are present in muscle cells and how they are regulated in T2D we will also investigate their function. Our most important approach to achieve this goal is to silence these microRNAs in animal models using pharmacological inhibitors, called antagomirs.