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

Author

Hain, Brian A., Xu, Haifang, Wilcox, Jenna R., Mutua, Daniel, and Waning, David L.

Subjects
Cachexia, Muscle function, Bone metastases, Chemotherapy, Article
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 105 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.

Published
2019

10. Zoledronic Acid Improves Muscle Function in Healthy Mice Treated with Chemotherapy.

Author

Hain, Brian A, Jude, Baptiste, Xu, Haifang, Smuin, Dallas M, Fox, Edward J, Elfar, John C, and Waning, David L

Abstract

Carboplatin is a chemotherapy drug used to treat solid tumors but also causes bone loss and muscle atrophy and weakness. Bone loss contributes to muscle weakness through bone‐muscle crosstalk, which is prevented with the bisphosphonate zoledronic acid (ZA). We treated mice with carboplatin in the presence or absence of ZA to assess the impact of bone resorption on muscle. Carboplatin caused loss of body weight, muscle mass, and bone mass, and also led to muscle weakness as early as 7 days after treatment. Mice treated with carboplatin and ZA lost body weight and muscle mass but did not lose bone mass. In addition, muscle function in mice treated with ZA was similar to control animals. We also used the anti‐TGFβ antibody (1D11) to prevent carboplatin‐induced bone loss and showed similar results to ZA‐treated mice. We found that atrogin‐1 mRNA expression was increased in muscle from mice treated with carboplatin, which explained muscle atrophy. In mice treated with carboplatin for 1 or 3 days, we did not observe any bone or muscle loss, or muscle weakness. In addition, reduced caloric intake in the carboplatin treated mice did not cause loss of bone or muscle mass, or muscle weakness. Our results show that blocking carboplatin‐induced bone resorption is sufficient to prevent skeletal muscle weakness and suggests another benefit to bone therapy beyond bone in patients receiving chemotherapy. © 2019 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Published
2020
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13. Abstract 3657: Identification of active metabolites of docosohexaenoic acid (DHA): A first step towards unraveling the fish oil/breast cancer conundrum.

Author

Manni, Andrea, primary, Richie, John P., additional, Trushin, Neil, additional, Prokopczyk, Bogdan, additional, Patterson, A, additional, Vanden Heuvel, John P., additional, Washington, Sharlene, additional, Xu, Haifang, additional, Aliaga, Cesar, additional, Das, Arunangshu, additional, Gowda, Krishne, additional, Amin, Shantu, additional, Liao, Jason, additional, Thompson, Henry, additional, and El-Bayoumy, Karam, additional

Published
2013
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15. Abstract 5571: Effects of fish oil and Tamoxifen on preneoplastic lesion development and biomarkers of oxidative stress in the early stages of N-methyl-N-nitrosourea-induced rat mammary carcinogenesis

Author

Manni, Andrea, primary, Richie, John P., additional, Xu, Haifang, additional, Washington, Sharlene, additional, Aliaga, Cesar, additional, Cooper, Timothy K., additional, Bruggeman, Richard, additional, Prokopczyk, Bogdan, additional, Calcagnotto, Ana, additional, Trushin, Neil, additional, Liao, Jason, additional, Verderame, Michael F., additional, and El-Bayoumy, Karam, additional

Published
2011
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16. Abstract 3710: Individual and combined effects of Tamoxifen and fish oil on mammary carcinogenesis in polyoma middle T transgenic mice

Author

Manni, Andrea, primary, Xu, Haifang, additional, Washington, Sharlene, additional, Aliaga, Cesar, additional, Cooper, Timothy K., additional, Richie, John P., additional, Prokopczyk, Bogdan, additional, Calcagnotto, Ana, additional, Trushin, Neil, additional, Hamilton, Christopher, additional, Demers, Laurence M., additional, Liao, Jason, additional, Verderame, Michael F., additional, and El-Bayoumy, Karam, additional

Published
2011
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17. Abstract 5578: Transcriptomic changes in tamoxifen-treated mammary tumors in Sprague-Dawley rats fed with omega-3 or omega-6 rich diets

Author

Bidinotto, Lucas T., primary, Vanegas, Johana E., additional, Vanden Heuvel, John P., additional, de Cicco, Ricardo Lopez, additional, Santucci-Pereira, Julia, additional, Washington, Sharlene, additional, Xu, Haifang, additional, Russo, Irma H., additional, El-Bayoumy, Karam, additional, Manni, Andrea, additional, and Russo, Jose, additional

Published
2011
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19. The Impact of Fish Oil on the Chemopreventive Efficacy of Tamoxifen against Development of N-Methyl-N-Nitrosourea–Induced Rat Mammary Carcinogenesis

Author

Manni, Andrea, primary, Xu, Haifang, additional, Washington, Sharlene, additional, Aliaga, Cesar, additional, Cooper, Timothy, additional, Richie, John P., additional, Bruggeman, Richard, additional, Prokopczyk, Bogdan, additional, Calcagnotto, Ana, additional, Trushin, Neil, additional, Mauger, David, additional, Verderame, Michael F., additional, and El-Bayoumy, Karam, additional

Published
2010
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20. Prediction of pulmonary arterial wedge pressure from arterial pressure or pulse oximetry plethysmographic waveform.

Author

Xu H, Zhou S, Ma W, and Yu B

Subjects
Adult, Aged, Humans, Middle Aged, Oximetry, Plethysmography, Positive-Pressure Respiration, Blood Pressure Determination methods, Pulmonary Wedge Pressure
Abstract

Objective: To assess the possibility of using arterial pressure waveform or pulse oximetry plethysmographic waveform variation to estimate the pulmonary arterial wedge pressure (PAWP)., Methods: Fourteen American Society of Anesthesiologists grade I - II patients aged 33 - 69 years and weighing 62.0 +/- 9.5 kg scheduled for elective abdominal tumor surgery were studied. Their hemoglobin exceeded 120 g/L and hematocrit exceeded 35 percent. Pre-operative acute hypervolemic hemodilution was applied immediately after general anesthestic induction and tracheal intubation. PAWP, systolic pressure variation (SPV), delta down (dDown), SPV(plet), dDown(plet) and other hemodynamic parameters were measured and recorded when total fluid volume (crystalloid and colloid) infused reached 10 ml/kg and 20 ml/kg and again at the end of the operation. Central venous pressure was maintained at 10 - 12 mm Hg during operation. Systolic blood pressure at the end of Valsalva maneuver (airway pressure was kept at 22 mm Hg) and the systolic pressure before the Valsalva manoeuvre during apnea were used to calculate arterial pressure ratio (APR)., Results: APR, SPV, dDown, SPV(plet) and dDown(plet) all correlated well with PAWP (r = 0.717, -0.695, -0.680, -0.522 and -0.624 respectively, P < 0.01). There was a closer linear correlation between APR and PAWP than between the other parameters. The regression equation was PAWP (mm Hg) = 0.207 x APR (%) - 0.382., Conclusion: During positive pressure mechanical ventilation, APR, SPV, dDown, SPV(plet) and dDown(plet) can be used to estimate PAWP effectively.

Published
2002

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