Axon-glia metabolic coupling of peripheral nerves in a rodent model of Charcot-Marie-Tooth 1A (CMT1A)
Axon-glia interaction extends beyond myelination itself. In the PNS, Schwann cells (SC) support axons with metabolites and trophic factors. In numerous disease models, primary glial mutations result in the collapse of normal nerve conduction. Understanding the details of metabolic coupling in health and its alteration in diseases may promote novel therapeutic targets. In patients as well as in the rat model of Charcot-Marie-Tooth disease type 1A (CMT1A) ("CMT rats"), an overexpression of peripheral myelin protein 22 (Pmp22) in SC results in severely reduced nerve conduction velocities and muscle weakness. Studies in CMT rats have shown pathological alterations in SC integrity secondarily leading to axonal dysfunction and eventually muscle atrophy. We hypothesized that under disease conditions the challenged SC is no longer able to metabolically support the axonal function. RNAseq analysis in CMT rats revealed differential regulation of metabolic pathway related genes. Metabolomics confirmed alterations in the metabolic steady state in nerves of nine weeks old CMT1A rats. Combining these two "omics" approaches, we could show a down regulation of the polyol pathway, glycolysis and TCA cycle. EM based analysis of axonal mitochondria in CMT1A motor fibers revealed increased numbers and an increase in size of the mitochondria in demyelinated fibers. Together, this suggests a failed energy status of the glial compartment. Interestingly, Glucose levels were significantly increased in whole nerve lysates, prompting closer investigation of glucose transporter 1 (GLUT1) in peripheral nervous tissue. We could localize GLUT1 to SC membranes and Schmidt-Lanterman incisures (SLI), indicative of a "direct" glucose supply to the axon. We hypothesize that in disease state the SC no longer supplies the axon with glycolysis end products. Free glucose may be used in the axonal compartment directly to uphold nerve conduction. However, with progressing demyelination energy needs may no longer be met, leading to axonal failure.
Electron Micrograph of Sciatic nerve in a CMT1A animal displaying the typical onion bulb formation (additional Schwann cells around a single axon)
Electron Micrograph of Femoral nerve in a CMT1A animal showing enlarged mitochondria in the axon.
Teased fiber preparation of sciatic nerve stained for MAG(red) labeling Schmidt-Lanterman incisures and Glucose Transporter 1 (GLUT1) in green.