Myelinating Schwann cells use Warburg effect to sustain axonal physiology and function

Summary Whether glial cells use a particular metabolism to support axonal metabolism and function remains controversial. We show here that the deletion of PKM2, an enzyme essential for the Warburg effect, in mature myelinating Schwann cells (mSC) of mice leads to a deficit of lactate in these cells and in peripheral nerves, and to motor defects despite no alteration of the myelin sheath. When electrically stimulated, peripheral nerve axons of mutant mice failed to maintain lactate homeostasis, resulting in an impaired production of mitochondrial ATP. Action potential propagation was not changed but axonal mitochondria transport was altered, muscle axon terminals retracted and motor neurons showed cellular stress. Further reducing lactate availability through dichloroacetate treatment definitely aggravated axonal malfunction in mutant mice. Thus, cancer-like Warburg effect is essential in mSC for the long term maintenance of peripheral nerve axons physiology and function. One Sentence Summary Lactate-dependent axons rely on cancer-like metabolism in myelinating Schwann cells.