Inhibition of Ornithine Decarboxylase 1 Mitigates Denervation‐Induced Muscle Atrophy by Suppressing Proteolysis and Preserving Muscle Stem Cell Homeostasis

ABSTRACT Neural innervation is of vital importance for muscle mass and function, and denervation induces progressive muscle atrophy, which lacks effective treatments. Polyamine metabolism is reported to be innervation responsive and involved in denervation‐induced muscle atrophy, yet the effects of polyamine in denervated muscle atrophy remain unknown. In this study, using a sciatic nerve transection model, we observed progressive increases in putrescine and spermidine, alongside induction of polyamine metabolism enzymes, coincident with the early rapid atrophy phase post denervation. Pharmacological ODC1 inhibition lowered intramuscular polyamines and improved denervated muscle atrophy and fibrosis. In contrast, spermidine supplementation induced muscle atrophy and atrogene expression in healthy and denervated muscle, implicating spermidine as a pro‐atrophic metabolite. Single‐nucleus sequencing revealed an expansion of atrophic myonuclei and depletion of type IIb myonuclei post denervation. DFMO reduced the atrophic myonuclear fraction, increased MuSCs abundance, and suppressed FAPs derived FGF signalling dominated by the Fgf7‐Fgfr2 axis to maintain MuSCs homeostasis. Taken together, our results demonstrate that dysregulated polyamine metabolism is a key contributor to denervation‐induced muscle atrophy, and ODC1 inhibition mitigates muscle atrophy and fibrosis by restraining proteolysis and preserving MuSCs homeostasis, which will provide references for future clinical treatments.