Understanding Glycogen Metabolism to Improve Functional Recovery After SCI

Close to 60% of all spinal cord injuries (SCI) occur at the cervical level. At this level are the phrenic motor neurons which innervate the diaphragm. Therefore, injuries at this level can lead to the inability to breathe, reliance on a mechanical ventilator in order to survive, and a reduced quality of life. The overall objective of this grant proposal is to examine the critical role with which glycogen plays in restoring breathing function after SCI. A multibranched polysaccharide of glucose, glycogen has a multifaceted role which includes maintaining carbohydrate storage, initiating neural and synaptic plasticity, and providing for mitochondrial energetics. If glycogen metabolism is altered or its synthesis blocked, these essential processes are disrupted or at worse, made pathological. In our preliminary studies there is an acute increase in glycogen levels followed by a decrease at chronic stages following experimental SCI correlating with the onset of spontaneous recovery and enhanced efficacy of therapeutic treatments. Moreover, when glycogen levels and availability is increased in transgenic animals there is a significant level of respiratory motor recovery and ventilatory patterns are closer to normal, pre-injury levels. Collectively, these studies suggest an essential role for glycogen in the restoration of function after SCI. It is our central hypothesis that enhancing glycogen availability and utilization after SCI will promote and improve functional recovery. This grant proposal seeks to: 1) define the temporal and spatial dynamics of CNS glycogen after cervical SCI; and 2) improve glycogen utilization through clinically relevant enzymatic therapies and enhance or restore respiratory motor recovery after SCI. Towards these aims we have assembled a highly experienced team in SCI, respiratory physiology, glycogen biology, and metabolomics which can achieve these goals. Overall, these studies will provide insight on the basic mechanisms that underlie recovery after SCI that can potentially lead to robust clinical therapies and strategies.