Chemotherapy‐induced loss of bone and muscle mass in a mouse model of breast cancer bone metastases and cachexia

Abstract

Background Chemotherapy used to treat malignancy can lead to loss of skeletal muscle mass and reduced force production, and can reduce bone volume in mice. We have shown that bone-muscle crosstalk is a key nexus in skeletal muscle function and bone homeostasis in osteolytic breast cancer bone metastases. Because chemotherapy has significant negative side effects on bone mass, and because bone loss can drive skeletal muscle weakness, we have examined the effects of chemotherapy on the musculoskeletal system in mice with breast cancer bone metastases. Methods and results Six-week-old Female athymic nude mice were inoculated with 10 5 MDA-MB231 human breast cancer cells into the left ventricle and bone metastases were confirmed by X-ray. Mice were injected with carboplatin at a dose of 60mg/kg once per week starting 4 days after tumor inoculation. Skeletal muscle was collected for biochemical analysis and extensor digitorum longus (EDL) whole muscle contractility was measured. The femur and tibia bone parameters were assessed by microCT and tumor burden in bone was determined by histology. Healthy mice treated with carboplatin lose whole body weight and have reduced individual muscle weights (gastrocnemius, tibialis anterior (TA), and EDL), reduced trabecular bone volume (BV/TV), and reduced EDL function. Mice with MDA-MB-231 bone metastases treated with carboplatin lose body weight, and have reduced EDL function as healthy mice treated with carboplatin. Mice with MDA-MB-231 bone metastases plus carboplatin do have reduced proximal tibia BV/TV compared to carboplatin alone, but carboplatin does reduce tumor burden in bone. Conclusions Our data shows that carboplatin treatment, aimed at reducing tumor burden, contributes to cachexia and trabecular bone loss. The muscle atrophy and weakness may occur through bone-muscle crosstalk and would lead to a feed-forward cycle of musculoskeletal degradation. Despite anti-tumor effects of chemotherapy, musculoskeletal impairment is still significant in mice with bone metastases.

Zoledronic Acid Improves Muscle Function in Healthy Mice Treated with Chemotherapy

“…Our previous findings showed loss of skeletal muscle and trabecular bone in mice treated with carboplatin for 28 days. (11) In this study, we showed that carboplatin causes loss of skeletal muscle and trabecular bone in mice in as little as 7 days. The mechanism of chemotherapy-induced bone loss is not fully understood and differs depending on the chemotherapy drug.…”

“…(10) Our previous work has shown that carboplatin treatment in healthy mice causes cachexia-like symptoms including loss of body mass, muscle atrophy, muscle weakness, and loss of bone. (11) Bone loss and muscle weakness caused by carboplatin treatment is not widely studied, and there is strong evidence that weakness can be caused by excessive bone resorption through the release of bone-derived cytokines. (12) Patients treated with various chemotherapy drugs including, combination cyclophosphamide/methotrexate/5-fluorouracil (CMF), combination 5-fluorouracil/doxorubicin/cyclophosphamide (FAC), doxorubicin/cyclophosphamide (AC), or cisplatin (13) experience reduced bone mineral density (BMD), which puts them at higher risk of bone fracture compared to people not treated with chemotherapy.…”

Formation of colorectal liver metastases induces musculoskeletal and metabolic abnormalities consistent with exacerbated cachexia

“…CRC (23,(26)(27)(28). Interestingly, the traditional C26 allograft model does not present with significant bone disruption (28).…”

Cancer‐ and Chemotherapy‐Induced Musculoskeletal Degradation

“…In particular, preclinical studies of breast cancer bone metastases have shed much light on this topic. Doxorubicin and carboplatin chemotherapies have been used to study musculoskeletal changes and have revealed that these agents alone cause significant reduction in bone volume . The combination therapy Folfiri (5‐fluorouracil, leucovorin, and irinotecan) also causes reduced bone volume …”

“…The common chemotherapy, cisplatin, has been shown to cause muscle atrophy that is associated with activation of NF‐κB signaling pathway and independent of the well‐characterized activation of ubiquitin proteosomal degradation . Another platinum coordinating therapy, carboplatin, has also been shown to lead to muscle wasting . Doxorubicin causes skeletal muscle weakness in part through a tumor necrosis factor receptor (TNFR1)‐dependent manner .…”