Evaluation of skeletal muscle function in male rats with doxorubicin-induced myopathy following various exercise techniques: the significant role of glucose transporter 4

Abstract

A common anthracycline antibiotic used to treat cancer patients is doxorubicin (DOX). One of the effects of DOX therapy is skeletal muscle fatigue. Our goal in this research was to study the beneficial effect of exercise on DOX-induced damaged muscle fibers and compare the effect of different exercise strategies (prophylactic, post- toxicity and combined) on DOX toxicity. Five groups were created from 40 male rats: group I, control group; group II, DOX was administered intraperitoneally for 2 weeks over 6 equal injections (each 2.5 mg/kg); group III, rats trained for 3 weeks before DOX; group IV, rats trained for 8 weeks after DOX; and group V, rats were trained for 3 weeks before DOX followed by 8 weeks after. Measures of oxidative damage (H₂O₂, catalase), inflammation (TNF-α), and glucose transporter 4 (GLUT4) expression on skeletal muscle were assessed. Also, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) was estimated. Skeletal performance was evaluated by contraction time (CT), half relaxation time (1/2 RT), and force-frequency relationship by the end of this research. The current study demonstrated a detrimental effect of DOX on skeletal performance as evidenced by a significant increase in CT and 1/2 RT compared to control; in addition, H₂O₂, TNF-α, and HOMA-IR were significantly increased with a significant decrease in GLUT4 expression and catalase activity. Combined exercise therapy showed a remarkable improvement in skeletal muscle performance, compared to DOX, CT, and 1/2 RT which were significantly decreased; H₂O₂ and TNF-α were significantly decreased unlike catalase antioxidant activity that significantly increased; in addition, skeletal muscle glucose metabolism was significantly improved as GLUT4 expression significantly increased and HOMA-IR was significantly decreased. Exercise therapy showed significant improvement in all measured parameters relative to DOX. However, combined exercise therapy showed the best improvement relative to both pre-exercise and post-exercise groups.

Keywords: Doxorubicin; Exercise; Fatigue; Insulin resistance; Muscle atrophy; Myopathy.

Fig. 1

Clustered column showing force generated at 1, 15, 30, 60, and 120 Hz in different groups

Fig. 2

Photomicrographs of a control, b DOX, c pre-E, d post-E, and e CE groups (H&E, 400 × scale bar = 20 μm). Green arrow: oval peripheral vesicular nuclei. T: transverse striations. Thin arrows: endomysium. Triangles: sarcoplasm striation. Black arrows: darkly stained pyknotic nuclei. Stars: loss of myofibrils. Blue arrows: centrally located nuclei