Skeletal Muscle Deconditioning in Breast Cancer Patients Undergoing Chemotherapy: Current Knowledge and Insights From Other Cancers

Abstract

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.

Chemotherapy impairs skeletal muscle mitochondrial homeostasis in early breast cancer patients

“…Specifically, this study identified four major mitochondrial alterations: (i) a striking reduction in the mitochondrial biogenesis marker PGC‐1α1, (ii) altered mitochondrial dynamics through weakened fusion process and potential mitophagy defects, (iii) exacerbated mitochondria‐mediated H 2 O 2 production, and (iv) an initiation of the apoptosis pathway. All of these alterations likely explain, at least in part, the high prevalence of cardiorespiratory deconditioning classically observed in breast cancer patients 2 . Therefore, the characterization of mitochondrial alterations may help researchers and clinicians identify appropriate therapeutic interventions to counteract skeletal muscle deconditioning.…”

“…Anthracycline/cyclophosphamide‐based and taxane‐based chemotherapies (CT) are commonly administered as (neo)adjuvant therapies to treat patients with early breast cancer 1 . Adverse events related to treatments have been extensively reported, including skeletal muscle deconditioning 2,3 . Resulting from a global perturbation of muscle homeostasis, skeletal muscle deconditioning is characterized by both structural and functional alterations that will translate into a decrease in muscle mass and/or force as well as an increase in muscle fatigability 2,4,5 .…”

“…In this context, skeletal muscle mitochondrial alterations appear to represent a major event implicated in muscle deconditioning and may explain the high prevalence of cardiorespiratory deconditioning classically observed in patients treated for early breast cancer 2 . However, very few clinical studies have been conducted to explore the underlying mechanisms.…”

“… 2 , 4 , 5 Skeletal muscle mitochondrial dysfunction and overall metabolic alterations represent another important aspect of skeletal muscle deconditioning, 6 , 7 , 8 a maladaptation known to reduce the quality of life and contributing to an increased overall treatment‐related toxicity that ultimately leads to a higher mortality risk. 2 , 9 , 10 , 11 …”

“…In this context, skeletal muscle mitochondrial alterations appear to represent a major event implicated in muscle deconditioning and may explain the high prevalence of cardiorespiratory deconditioning classically observed in patients treated for early breast cancer. 2 However, very few clinical studies have been conducted to explore the underlying mechanisms. Therefore, this study was dedicated to investigating overall skeletal muscle mitochondrial homeostasis in early breast cancer patients treated by CT, including mitochondrial quantity, function, and dynamics.…”