Compound muscle action potential as an early functional in vivo measure of Sarm1 inhibition after sciatic nerve transection

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The NADase sterile alpha and TIR motif containing 1 (Sarm1) protein drives axon degeneration after injury. Loss or inhibition of Sarm1 structurally protects axons after sciatic nerve transection (SNT) in vivo but whether Sarm1 also drives functional loss after nerve injury is less clear. We established compound muscle action potential (CMAP) as a novel functional correlate of Sarm1 activation in a SNT mouse model and evaluated its relationship with biochemical and a novel Cellpose-based histological axon detection measure. CMAP amplitudes were elicited 8 h post-SNT but reached near-floor levels by 24 h. Decreases in CMAP amplitude are delayed in a gene dose-dependent manner in Sarm1 knockout mice or by pharmacological Sarm1 inhibition. Myelinated axon density, the NAD hydrolysis product cyclic adenosine diphosphate ribose (cADPR), and the axon degeneration plasma biomarker neurofilament light (NfL) were all altered in a Sarm1-dependent manner. In wild type mice, axon density and NfL were altered at time points after that of cADPR and functional loss, indicating that functional deficits preceded structural deficits. We conclude that functional and structural declines after injury are delayed by Sarm1 inhibition and that CMAP measures after SNT can serve as a novel, preclinical, functional, pharmacodynamic readout for Sarm1 inhibition.

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