Effect of HIF-1α inhibitors for preventing the progress of muscle contracture in rat soleus muscles

Abstract

Immobilization-induced muscle fibrosis is important regarding the pathogenesis of muscle contracture, and the therapeutic target for this fibrotic lesion is unknown. On the other hand, hypoxia-inducible factor (HIF)-1α is expected to be a new therapeutic target for fibrotic disease in the viscera. Accordingly, preventing the negative alteration of HIF-1α may suppress the progress of immobilization-induced muscle fibrosis. Therefore, this study investigated the effect of the HIF-1α inhibitor for immobilization-induced muscle fibrosis in rat soleus muscles. Wistar rats were randomly divided into control and experimental groups. In the experimental group, both ankle joints were fixed in full plantar flexion with plaster casts for 4 weeks. Some rats in the experimental group were immobilized throughout the 4-week period (immobilization group), whereas other rats in the experimental group were treated with YC-1, an HIF-1α inhibitor (YC-1 group). Additionally, YC-1 (2 mg/mL/day) was administered to each rat for 4 weeks. Bilateral dorsiflexion range of motion (ROM) in the ankle joints was measured each week to evaluate muscle contracture. Moreover, hydroxyproline (a parameter for collagen contents) and protein levels of HIF-1α were determined via biochemical analysis. Dorsiflexion ROM was significantly smaller in both experimental groups than in the control group at each timepoint, whereas this parameter was significantly greater in the YC-1 group than in the immobilization group after 3 weeks. In addition, the hydroxyproline and HIF-1α protein were significantly greater in the immobilization and YC-1 groups than in the control group at 4 weeks. However, both expressions were significantly smaller in the YC-1 group than in the immobilization group at 4 weeks. From these results, the HIF-1α inhibitor may prevent immobilization-induced muscle fibrosis leading to muscle contracture. We surmised that the HIF-1α inhibition is a new therapeutic target for muscle contracture in immobilized skeletal muscle.