Doksorubisin ile Oluşturulan Deneysel İskelet Kası Atrofisi Modelinde Mitokondri Transplantasyonu ve Egzersizin Etkileri

Abstract

Doxorubicin (DOX) is a chemotherapy drug that serves to treat many different forms of cancer but has hazardous side effects. It has been demonstrated in several studies that its toxic effect induces skeletal muscle atrophy. Exercise prevents skeletal muscle atrophy, particularly via mitochondrial pathways, without altering DOX's antineoplastic effects. While mitochondria transplantation may mitigate toxicity, neurological disorders, heart, kidney, and liver damage, its effects on skeletal muscle atrophy remain unknown. The goal of the study was to assess how exercise and mitochondrial transplantation affected recovery in a rat model of DOX-induced skeletal muscle atrophy. In this study, male Sprague Dawley rats were divided into control (K), DOX (D), DOX and mitochondria (DM), DOX and exercise (DE), DOX, exercise and mitochondria (DEM) groups (n=8/group). Before receiving a dosage of DOX, the rats in the exercise group (DE) underwent a 10-day running exercise whereas those in the mitochondrial group (DM) received two doses of mitochondrial transplantation. In the exercise and mitochondria group (DEM), both exercise and mitochondria transplantation were applied together. The D, DM, DE, and DEM groups received a 20 mg/kg DOX injection to induce muscular atrophy. MitoTracker Red CMXROS, MitoSpy Green FM, and JC-1 analysis were performed for the membrane integrity and potential of the isolated mitochondria. In the tibialis anterior muscle, measurement of muscle weights, histological analysis (H-E, SDH, and PAS), immunohistochemical analysis (Caspase-3, NF-κB, DRP-1, and MFN-2), biochemical analysis of blood samples (urea, LDH, ALT, and AST) and oxidative stress analysis (TAS and TOS) were performed. When the tibialis anterior muscle weights of the groups were compared DE and DEM groups increased significantly compared to the K group (P < 0.05). When the final body weights were compared, the DM, DE, and DEM groups increased significantly compared to the D group (P < 0.05). For the tibialis anterior cross-sectional area, the D group decreased compared to the K group, DE and DEM groups increased compared to the D group (P < 0.05). SDH levels were found to be significantly higher in all groups compared to the group D (P < 0.05). Urea levels were higher in D and DM groups compared to the K group, but significantly lower in the DE group (P < 0.05), and ALT levels were significantly higher in DM, DE, DEM groups compared to the K group (P < 0.05). Caspase-3 level was found to be significantly higher in D and DM groups compared to DE and DEM groups (P < 0.05), while NF-kB level was higher in D group than K group, and lower in DM, DE, DEM groups compared to D group (P < 0.05). DRP-1 level was higher in D and DE groups than K group and was lower in DM and DEM groups than D group (P < 0.05). MFN-2 level was higher in DM and DE groups than the K group and was higher in the DE group than the D group (P < 0.05). DE group was lower than K and DM groups in the TOS analysis, while DE and DEM groups were higher than the K group in the TAS analysis (P < 0.05). These results demonstrated that the role of exercise in preventing muscle atrophy is important, but it is more effective with mitochondria transplantation.