TSPO PET selectively detects the denervated skeletal muscle district remodeling after experimental peripheral nerve injury

Abstract

Abstract Background Peripheral nerve injury induces inflammatory and stress-related remodeling in downstream skeletal muscle before overt atrophy develops, yet non-invasive approaches capable of detecting and anatomically localizing early muscle involvement remain limited. The 18-kDa translocator protein (TSPO), a marker of inflammatory activation and mitochondrial stress, is a molecular target for PET imaging with [¹⁸F]DPA-714. This study aimed to determine whether TSPO-targeted PET imaging enables early and spatially resolved detection of denervation-induced skeletal muscle injury distal to a peripheral nerve lesion. Results Adult mice underwent unilateral sciatic nerve crush. One-week post-injury, static [¹⁸F]DPA-714 PET imaging was performed to assess tracer uptake in hindlimb skeletal muscle. Uptake was quantified and compared between injured and contralateral limbs as well as with sham-operated mice. Ex vivo validation included CD68 immunofluorescence, Western blot analysis of TSPO expression, and laminin-based muscle fiber morphometry. [¹⁸F]DPA-714 uptake was significantly increased in distal hindlimb of crush-injured mice compared with contralateral and sham models. PET signal was selectively confined to denervated muscle distal to the lesion. Tracer uptake ratio between injured and contralateral hindlimb clearly discriminated crush-injured from sham animals without overlap. Immunofluorescence demonstrated marked macrophage infiltration, Western blot confirmed increased TSPO protein levels, and laminin morphometry revealed reduced muscle fiber size consistent with early atrophic remodeling. Conclusions TSPO-targeted PET with [¹⁸F]DPA-714 enables an early and anatomically selective detection of denervation-induced skeletal muscle injury distal to the nerve lesion, supporting its role as a translational imaging biomarker of peripheral nerve-muscle interaction during acute reversible nerve damage .