Role of skeletal muscle IPMK in nutrient metabolism and exercise

SUMMARY Inositol phosphates are critical signaling messengers involved in a wide range of biological pathways in which inositol polyphosphate multikinase (IPMK) functions as a rate limiting enzyme for inositol polyphosphate metabolism. Many laboratories including ours have studied the biology of IPMK mostly in cellular models. IPMK has been implicated in metabolism but its tissue-specific function at the systemic level is poorly understood. IPMK is highly expressed in skeletal muscle, and the levels are increased with exercise and decreased in diabetes. Skeletal muscle is a major contributor to energy homeostasis, therefore, we have developed mouse and cellular models to elucidate metabolic mechanisms of IPMK. We have found that mice in which IPMK is specifically deleted in skeletal muscle (MKO) displayed disrupted nutrient utilization, impaired glucose tolerance and reduced exercise tolerance compared to the control mice. Moreover, global metabolic and biochemical analyses revealed disrupted mitochondrial functions, reduced beta-oxidation and impaired insulin response in ipmk deficient muscle cells. In addition, we found that IPMK regulates the levels of acetylation via histone protein deacetylases, which plays a key role in metabolism. Based on our previous research and preliminary data, we hypothesize that skeletal muscle IPMK plays critical roles in nutrient utilization and energy homeostasis. We propose four specific aims. In Aim 1, we will investigate the in vivo actions of muscle IPMK on fuel utilization at rest and during exercise. In Aim 2, we will examine how muscle IPMK regulates whole-body metabolism and its response to exercise. In Aim 3, we will investigate how IPMK regulates nutrient utilization in myocytes using biochemical, cellular and molecular approaches combined with chemical genetics to modulate IPMK activity. In Aim 4, we will investigate the transcriptional mechanisms by which IPMK modulates energy utilization using biochemical, transcriptomic and bioinformatic approaches. Together, this project is expected to advance the field by filling a critical gap in understanding of the biology of IPMK in energy homeostasis. Our proposed studies will illuminate the key functions of skeletal muscle in metabolism and could potentially lead to the development of new therapies for diabetes, obesity and related diseases.