Impairments in mitochondrial dynamics and morphology in skeletal muscle of breast cancer patients after a single paclitaxel administration

Abstract

Standard chemotherapy regimens for patients with breast cancer are based on epirubicin–cyclophosphamide (EC) and paclitaxel (TAX) administrations. While it has been shown that first EC administration impairs mitochondrial homeostasis, the isolated effects of TAX have not been studied without previous chemotherapy exposure. We conducted a prospective clinical study including five patients with breast cancer who underwent two vastus lateralis muscle biopsies before and 4 days after the first TAX administration, without any prior chemotherapy exposure. Mitochondrial respiratory capacity, reactive oxygen species production, mitochondrial dynamics and ultrastructure, and apoptosis were assessed using high‐resolution respirometry, western blotting, transmission electron microscopy, and TUNEL assay, respectively. Post‐TAX, the number of intermyofibrillar mitochondria decreased (−18%; P  = 0.049), while the proportion of damaged mitochondria increased (+34%; P  = 0.012). Mitochondrial area, perimeter and major/minor axis lengths increased ( P  < 0.05) while intermyofibrillar cristae area decreased (4.29% pre‐TAX vs. 2.60% post‐TAX; P  = 0.044). Despite these morphological changes, oxidative phosphorylation capacity and respiratory control ratio remained unchanged, whereas complex I‐linked substrate respiration decreased (−29%; P  = 0.046). MFN2 (−43%; P  = 0.040) and Fis1 (−46%; P  = 0.046) protein levels decreased post‐TAX while mitophagy markers were unchanged. Apoptosis was increased, as documented by increased Bax (+58%; P  = 0.045) and TUNEL‐positive nuclei (+395%; P  = 0.041). In only 4 days, the first TAX administration induced severe skeletal muscle mitochondrial remodelling in patients with breast cancer, characterized by impaired mitochondrial dynamics that resulted in swollen and damaged organelles. These findings demonstrate that mitochondrial toxicity, classically documented at the end of treatment, occurs acutely and after only one chemotherapy administration.