Monocarboxylate transporter 1 in Schwann cells contributes to maintenance of sensory nerve myelination during aging

• Published in: Glia 2020-01, Vol.68 (1), p.161-177
• Main Authors: Jha, Mithilesh Kumar, Lee, Youngjin, Russell, Katelyn A., Yang, Fang, Dastgheyb, Raha M., Deme, Pragney, Ament, Xanthe H., Chen, Weiran, Liu, Ying, Guan, Yun, Polydefkis, Michael J., Hoke, Ahmet, Haughey, Norman J., Rothstein, Jeffrey D., Morrison, Brett M.
• Format: Article
• Language: English
• Subjects: Aging; Aging - genetics; Aging - metabolism; Animals; Cells, Cultured; Clonal deletion; Female; Glycolysis; Glycoproteins; lactate; Lipid metabolism; Lipids; Maintenance; Male; Maturation; MCT1; Metabolism; Mice; Mice, Knockout; Mice, Transgenic; Mitochondria; monocarboxylate transporter; Monocarboxylic Acid Transporters - deficiency; Monocarboxylic Acid Transporters - genetics; Monocarboxylic Acid Transporters - metabolism; Myelin; Myelin P0 protein; Myelin Sheath - genetics; Myelin Sheath - metabolism; Myelination; Neural Conduction - physiology; peripheral nerve; Peripheral nerves; Schwann cell; Schwann cells; Schwann Cells - metabolism; sensory axons; Sensory neurons; Sensory Receptor Cells - metabolism; Sphingomyelin; Sural Nerve - metabolism; Symporters - deficiency; Symporters - genetics; Symporters - metabolism; triacylglycerides; Triglycerides
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.23710

Schwann cell (SC)‐specific monocarboxylate transporter 1 (MCT1) knockout mice were generated by mating MCT1 f/f mice with myelin protein zero (P0)‐Cre mice. P0‐Cre+/−, MCT1 f/f mice have no detectable early developmental defects, but develop hypomyelination and reduced conduction velocity in sensory, but not motor, peripheral nerves during maturation and aging. Furthermore, reduced mechanical sensitivity is evident in aged P0‐Cre+/−, MCT1 f/f mice. MCT1 deletion in SCs impairs both their glycolytic and mitochondrial functions, leading to altered lipid metabolism of triacylglycerides, diacylglycerides, and sphingomyelin, decreased expression of myelin‐associated glycoprotein, and increased expression of c‐Jun and p75‐neurotrophin receptor, suggesting a regression of SCs to a less mature developmental state. Taken together, our results define the contribution of SC MCT1 to both SC metabolism and peripheral nerve maturation and aging. Main Points SC MCT1 deficiency causes hypomyelination of sensory, but not motor, axons during aging. Selective ablation of MCT1 within SCs impairs glycolytic and mitochondrial functions. SC‐specific MCT1 deficiency impairs proteins that regulate myelin and lipid metabolism in peripheral nerves