Intramuscular inhibition of glycogen phosphorylase improves motor function in spinal cord injury

Motor dysfunction in various diseases and aging is often accompanied by skeletal muscle atrophy and reduced axonal projections from motor neurons to the skeletal muscles. While several studies have investigated the correlations and molecular mechanisms between muscle atrophy and motor neuron denervation to explain the pathology of motor diseases, it remains unclear whether skeletal muscle atrophy directly causes axonal denervation of motor neurons. Here, we used a casts-attached mouse model which represents muscle atrophy and motor dysfunction in the hindlimbs to explore how skeletal muscle atrophy affects motor neuronal axon projections. Retrograde neuronal tracing from the skeletal muscles to motor neurons revealed that axonal projections from motor neurons were reduced to the atrophied skeletal muscles compared to the healthy muscles. In addition, we identified glycogen phosphorylase (GP) as an upregulated protein in the plasma membrane of atrophied gastrocnemius muscles. The expression level of GP was also increased on the membrane of primary cultured myotubes treated with dexamethasone to induce muscle atrophy in vitro. Importantly, intramuscular injection of a GP inhibitor into the hindlimbs improved motor function in a mouse model of spinal cord injury. Furthermore, axonal projection from spinal cord neurons to dexamethasone-treated atrophied myotubes was reduced compared to healthy myotubes, whereas GP inhibitor treatment to atrophied myotubes promoted axonal growth of the spinal cord neurons overlayed on the myotubes. This study demonstrated that skeletal muscle atrophy induces attenuation of motor neuronal innervation and inhibition of GP in atrophied skeletal muscles may be a novel therapeutic approach for spinal cord injury by enhancing axonal projections from motor neurons to the skeletal muscles.