Versatile role of fibro-adipogenic progenitors in neuromuscular junction homeostasis and pathology.

The neuromuscular junction (NMJ) is a specialized synapse that enables reciprocal signaling between motor nerves and muscle fibers. NMJ integrity is essential for muscle homeostasis, while retrograde signals from muscle also modulate nerve axon physiology. Nerve injury or neuromuscular diseases often result in functional deficits and histological changes. Fibro-adipogenic progenitors (FAPs) are muscle-resident multipotent mesenchymal cells, and a large body of research illustrated their role in muscle mass maintenance and regeneration. Recently, FAPs have been suggested to be responsive to NMJ perturbations. However, many questions remain, including how FAPs sense nerve injury and neuropathology; what factors drive their fate determination; and what effectors mediate their responses to NMJ impairments. In this review, we first provide a brief overview of NMJ structure and formation, then discuss the role of FAPs in NMJ homeostasis, nerve injury, and neuromuscular diseases. FAPs regulate NMJ development and regeneration via paracrine factor secretion, extracellular matrix modulation, and cellular interaction. Aberrantly activated FAPs drive pathological muscle fibrosis, fatty-infiltration, and ectopic bone formation. This comprehensive perspective of FAP-NMJ interactions will shed a new light on NMJ regeneration mechanisms and neuromuscular disease control.