Loss of Skeletal Muscle Inositol Polyphosphate Multikinase Disrupts Glucose Regulation and Limits Exercise Capacity

Inositol phosphates are critical signaling messengers involved in a wide range of biological pathways, and inositol polyphosphate multikinase (IPMK) functions as a rate-limiting enzyme for inositol polyphosphate metabolism. IPMK has been implicated in cellular metabolism, but its function at the systemic level is still poorly understood. Since skeletal muscle is a major contributor to energy homeostasis, we have developed a mouse model in which skeletal muscle IPMK is specifically deleted and examined how a loss of IPMK affects whole-body metabolism. Here, we report that skeletal-muscle-specific IPMK knockout mice exhibited a ~12% increase in body weight compared to WT controls (p < 0.05). These mice also showed a significantly impaired glucose tolerance, as indicated by their ~50% higher blood glucose levels during GTT. Additionally, exercise capacity was reduced by ~45% in IPMK-MKO mice, demonstrating a decline in endurance. Moreover, these metabolic alterations were accompanied by a 2.5-fold increase in skeletal muscle triglyceride accumulation, suggesting impaired lipid metabolism. Further analysis revealed that IPMK-deficient myocytes exhibited 30% lower β-oxidation rates. Thus, our results suggest that IPMK mediates whole-body metabolism by regulating muscle metabolism and may be potentially targeted for the treatment of metabolic syndromes.