Background: Denervation induces muscle atrophy by accelerating myofibrillar protein catabolism, primarily through the ubiquitin-proteasome system, mediated by two E3 ubiquitin ligases: muscle atrophy F-box (MAFbx/atrogin-1) and muscle RING-finger protein-1 (MuRF-1). Both ligases act as early markers, reaching peak expression by day 3 post-injury, coinciding with the period of most rapid muscle loss following denervation. Pentoxifylline (PTX), a methylxanthine derivative that non-selectively inhibits PDE, has been shown to suppress the production of proinflammatory cytokines such as TNF-alpha, which mediate proteasome-dependent muscle catabolism. This study aims to assess whether oral PTX administration can mitigate early-stage denervation-induced muscle atrophy in a rat sciatic nerve denervation model. Methods:10 male Lewis rats, aged 8-10 weeks, underwent complete transection of the sciatic nerve followed by transposition to the anterior thigh and coaptation to the distal end of the divided femoral nerve to prevent spontaneous reinnervation of the denervated muscle groups. The rats were then randomly assigned to two groups: one receiving 100 mg/kg of PTX via oral gavage, and the other receiving no treatment (n=5 rats/group). At three days post-injury, the lateral gastrocnemius (LG) muscle was harvested and homogenized to assess Atrogin-1 and MuRF-1 levels using ELISA. Results: At three days post-denervation, PTX-treated LG muscle samples exhibited a significant reduction in Atrogin-1 levels (Median PTX: 1.55 pg/1ug protein, IQR: [0.29]; Median No treatment: 2.73 pg/1ug protein, IQR: [1.05], p=0.01), indicating a reduction of approximately 43.1% when compared to the untreated group. PTX-treated LG muscle samples also demonstrated a significant reduction in MuRF-1 levels (Median PTX: 3.91 pg/1ug protein, IQR: [1.09]; Median No treatment: 5.00 pg/1ug protein, IQR: [0.16], p=0.01), indicating a 20.2% decrease compared to the untreated group. Conclusion: The use of oral Pentoxifylline PTX shows promise in alleviating initial denervation-induced muscle atrophy.
