Background Chemotherapy is extensively used to treat breast cancer and is associated with skeletal muscle deconditioning, which is known to reduce patients' quality of life, treatment efficiency, and overall survival. To date, skeletal muscle mitochondrial alterations represent a major aspect explored in breast cancer patients; nevertheless, the cellular mechanisms remain relatively unknown. This study was dedicated to investigating overall skeletal muscle mitochondrial homeostasis in early breast cancer patients undergoing chemotherapy, including mitochondrial quantity, function, and dynamics. Methods Women undergoing (neo)adjuvant anthracycline-cyclophosphamide and taxane-based chemotherapy participated in this study (56 ± 12 years). Two muscle biopsies were collected from the vastus lateralis muscle before the first and after the last chemotherapy administration. Mitochondrial respiratory capacity, reactive oxygen species production, and western blotting analyses were performed. Results Among the 11 patients, we found a decrease in key markers of mitochondrial quantity, reaching À52.0% for citrate synthase protein levels (P = 0.02) and À38.2% for VDAC protein levels (P = 0.04). This mitochondrial content loss is likely explained by reduced mitochondrial biogenesis, as evidenced by a decrease in PGC-1α1 protein levels (À29.5%; P = 0.04). Mitochondrial dynamics were altered, as documented by a decrease in MFN2 protein expression (À33.4%; P = 0.01), a key marker of mitochondrial outer membrane fusion. Mitochondrial fission is a prerequisite for mitophagy activation, and no variation was found in either key markers of mitochondrial fission (Fis1 and DRP1) or mitophagy (Parkin, PINK1, and Mul1). Two contradictory hypotheses arise from these results: defective mitophagy, which probably increases the number of damaged and fragmented mitochondria, or a relative increase in mitophagy through elevated mitophagic potential (Parkin/VDAC ratio; +176.4%; P < 0.02). Despite no change in mitochondrial respiratory capacity and COX IV protein levels, we found an elevation in H 2 O 2 production (P < 0.05 for all substrate additions) without change in antioxidant enzymes. We investigated the apoptosis pathway and found an increase in the protein expression of the apoptosis initiation marker Bax (+72.0%; P = 0.04), without variation in the anti-apoptotic protein Bcl-2. Conclusions This study demonstrated major mitochondrial alterations subsequent to chemotherapy in early breast cancer patients: (i) a striking reduction in mitochondrial biogenesis, (ii) altered mitochondrial dynamics and potential mitophagy defects, (iii) exacerbated H 2 O 2 production, and (iv) increased initiation of apoptosis. All of these alterations likely explain, at least in part, the high prevalence of skeletal muscle and cardiorespiratory deconditioning classically observed in breast cancer patients.

Breast cancer represents the most commonly diagnosed cancer while neoadjuvant and adjuvant chemotherapies are extensively used in order to reduce tumor development and improve disease-free survival. However, chemotherapy also leads to severe off-target side-effects resulting, together with the tumor itself, in major skeletal muscle deconditioning. This review first focuses on recent advances in both macroscopic changes and cellular mechanisms implicated in skeletal muscle deconditioning of breast cancer patients, particularly as a consequence of the chemotherapy treatment. To date, only six clinical studies used muscle biopsies in breast cancer patients and highlighted several important aspects of muscle deconditioning such as a decrease in muscle fibers cross-sectional area, a dysregulation of protein turnover balance and mitochondrial alterations. However, in comparison with the knowledge accumulated through decades of intensive research with many different animal and human models of muscle atrophy, more studies are necessary to obtain a comprehensive understanding of the cellular processes implicated in breast cancer-mediated muscle deconditioning. This understanding is indeed essential to ultimately lead to the implementation of efficient preventive strategies such as exercise, nutrition or pharmacological treatments. We therefore also discuss potential mechanisms implicated in muscle deconditioning by drawing a parallel with other cancer cachexia models of muscle wasting, both at the pre-clinical and clinical levels.