Background <p>Denervation occurs as a consequence of disease or injury and is typically accompanied by skeletal muscle atrophy. Although the relationship between nerves and muscle atrophy has been studied, the direct molecular contributions of nerves remain unclear.</p> Methods <p>We used the axolotl (<i>Ambystoma mexicanum</i>), a vertebrate with robust regenerative capacity and optically accessible musculature, to investigate the role of nerve-derived signals in muscle maintenance.</p> Results <p>Forelimb denervation produced significant muscle atrophy in axolotls. Quantitative imaging showed that reduced muscle fiber size—rather than fiber loss—underlies this atrophy. To investigate the molecular basis of denervation-induced atrophy, we focused on fibroblast growth factor 2 (FGF2), a nerve-derived factor previously implicated in axolotl limb regeneration. Electroporation of FGF2 into denervated muscles significantly preserved muscle fiber size compared with controls. Conversely, pharmacological inhibition of FGF signaling with SU5402 reduced fiber size, supporting a requirement for FGF signaling in maintaining muscle mass.</p> Conclusions <p>These findings demonstrate that FGF2 is sufficient to mitigate denervation-induced muscle atrophy and support a requirement for FGF signaling in the maintenance of muscle mass. Together with the neural expression of <i>Fgf2</i>, our data support a model in which nerve-derived FGF2 contributes to muscle maintenance. This work positions the axolotl as a tractable model for dissecting neuromuscular signaling and identifies FGF2 as a promising therapeutic candidate for neuromuscular atrophy. Understanding this mechanism may inform strategies to preserve muscle mass after nerve injury or in neurodegenerative diseases.</p>