ActIIR inhibition improves motor outcome and preserves muscle fibers after experimental autoimmune neuritis.

Secondary muscle atrophy resulting from neuronal denervation is a key determinant of poor functional recovery in immune-mediated neuropathies, even after inflammation is resolved. While current immunotherapies effectively limit immune-mediated nerve injury, secondary muscle atrophy as a downstream consequence of denervation is not addressed by existing treatment strategies. Activin type II receptors (ActIIR) are central regulators of skeletal muscle atrophy, and pharmacological inhibition of ActIIR signaling has shown variable efficacy in primary myopathies. Here, we investigated the therapeutic potential of ActIIR inhibition in promoting motor recovery in immune-mediated neuropathies using experimental autoimmune neuritis, a rodent model of Guillain-Barré syndrome. At the onset of the recovery phase, animals received varying doses of a synthesized anti-ActIIR antibody. Motor performance was assessed using a standardized clinical neuritis score, grip strength testing, electrophysiological nerve conduction studies, and balance-beam performance combined with quantitative kinematic gait analysis. High-dose ActIIR antibody treatment significantly improved motor performance during the recovery phase. This improvement was not associated with detectable changes in peripheral nerve immune infiltration, inflammatory cytokine expression, or myelination, but correlated with preservation of muscle fiber size. Consistent with this, muscle proteomic and targeted transcriptional analyses revealed attenuation of FoxO-dependent atrophy programs and reduced expression of the E3 ubiquitin ligases Atrogin-1 and MuRF1. Together, these findings suggest that ActIIR inhibition limits secondary muscle atrophy and enhances motor recovery in autoimmune neuritis. Targeting ActIIR signaling may therefore represent a promising muscle-directed adjunct strategy to improve motor outcomes in immune-mediated neuropathies.