Exercise Intolerance in Anthracycline-Treated Breast Cancer Survivors: The Role of Skeletal Muscle Bioenergetics, Oxygenation, and Composition

Abstract

Background: Peak oxygen consumption (VO₂ ) is reduced in women with a history of breast cancer (BC). We measured leg blood flow, oxygenation, bioenergetics, and muscle composition in women with BC treated with anthracycline chemotherapy (n = 16, mean age: 56 years) and age- and body mass index-matched controls (n = 16).

Materials and methods: Whole-body peak VO₂ was measured during cycle exercise. ³¹ Phosphorus magnetic resonance (MR) spectroscopy was used to measure muscle bioenergetics during and after incremental to maximal plantar flexion exercise (PFE). MR imaging was used to measure lower leg blood flow, venous oxygen saturation (S_v O₂ ), and VO₂ during submaximal PFE, and abdominal, thigh, and lower leg intermuscular fat (IMF) and skeletal muscle (SM).

Results: Whole-body peak VO₂ was significantly lower in BC survivors versus controls (23.1 ± 7.5 vs. 29.5 ± 7.7 mL/kg/minute). Muscle bioenergetics and mitochondrial oxidative capacity were not different between groups. No group differences were found during submaximal PFE for lower leg blood flow, S_v O₂ , or VO₂ . The IMF-to-SM ratio was higher in the thigh and lower leg in BC survivors (0.36 ± 0.19 vs. 0.22 ± 0.07, p = .01; 0.10 ± 0.06 vs. 0.06 ± 0.02, p = .03, respectively) and were inversely related to whole-body peak VO₂ (r = -0.71, p = .002; r = -0.68, p = .003, respectively)_. In the lower leg, IMF-to-SM ratio was inversely related to VO₂ and O₂ extraction during PFE.

Conclusion: SM bioenergetics and oxidative capacity in response to PFE are not impaired following anthracycline treatment. Abnormal SM composition (increased thigh and lower leg IMF-to-SM ratio) may be an important contributor to reduced peak VO₂ during whole-body exercise among anthracycline-treated BC survivors.

Implications for practice: Peak oxygen consumption (peak VO₂ ) is reduced in breast cancer (BC) survivors and is prognostic of increased risk of cardiovascular disease-related and all-cause mortality. Results of this study demonstrated that in the presence of deficits in peak VO₂ 1 year after anthracycline therapy, skeletal muscle bioenergetics and oxygenation are not impaired. Rather, body composition deterioration (e.g., increased ratio of intermuscular fat to skeletal muscle) may contribute to reduced exercise tolerance in anthracycline BC survivors. This finding points to the importance of lifestyle interventions including caloric restriction and exercise training to restore body composition and cardiovascular health in the BC survivorship setting.

Keywords: Anthracyclines; Breast cancer; Intermuscular fat; Magnetic resonance imaging; Muscle bioenergetics; Oxygen uptake; Skeletal muscle.

Figure 1

Experimental MRI plantar flexion setup and image acquisition. (A): Experimental setup for plantarflexion exercise device. (B): Image acquisition for determination of lower leg VO₂, showing the typical location for imaging of the superficial femoral vein and representative S_vO₂ and blood velocity images, at rest and immediately after exercise. In this subject, S_vO₂ ≈ 86% at rest and 57% after exercise, with corresponding blood velocities of 7 cm/second and 25 cm/second. Abbreviations: S_vO₂, venous oxygen saturation; VO₂, oxygen consumption.

Figure 2

Magnetic resonance body composition acquisition and analysis by the modified Dixon fat–water separation approach in the lower leg (A), thigh (B), and abdomen (C) of a representative participant with low intermuscular fat and in the lower leg (D), thigh (E), and abdomen (F) of a representative participant with high intermuscular fat.

Figure 3

Relationship between IMF‐to‐SM ratio and whole‐body peak VO₂ for the paraspinal, thigh, and lower leg muscle regions. Abbreviations: IMF, intermuscular fat; SM, skeletal muscle; VO₂, oxygen consumption.