Longitudinal Changes in Skeletal Muscle Metabolism, Oxygen Uptake, and Myosteatosis During Cardiotoxic Treatment for Early-Stage Breast Cancer

BACKGROUND: While cardiotoxic chemotherapy is known to negatively impact cardiac function and hemoglobin levels, the impact on skeletal muscle has been understudied among patients. The purpose was to longitudinally characterize myosteatosis (muscle fat), skeletal muscle metabolism, and oxygen (O(2)) consumption during cardiotoxic chemotherapy for breast cancer. PATIENTS AND METHODS: Thirty-four patients with stage I-III breast cancer were enrolled before trastuzumab-containing and/or anthracycline-containing chemotherapy. We used magnetic resonance imaging to non-invasively quantify thigh myosteatosis (fat-water imaging), and lower leg metabolism ((31)P spectroscopy), O(2) consumption (custom techniques), and peak power output during single-leg plantarflexion exercise at pre-, mid-, end-chemotherapy, and 1-year. We also measured pulmonary VO(2)peak and maximal leg press strength. RESULTS: During chemotherapy, VO(2)peak and leg press strength decreased while peak plantarflexion power output was maintained. At mid-chemotherapy, hemoglobin decreased (16%) and lower leg blood flow increased (37%) to maintain lower leg O(2) delivery; exercise Pi:PCr and myosteatosis increased. Between mid- and end-chemotherapy, lower leg O(2) extraction (28%) and O(2) consumption (21%) increased, while plantarflexion exercise efficiency (watts/O(2) consumed) decreased. At one year, VO(2)peak and leg press strength returned to pre-chemotherapy levels, but lower leg exercise O(2) extraction, consumption and Pi:PCr, and myosteatosis remained elevated. CONCLUSION: Lower leg skeletal muscle blood flow and O(2) extraction adapt to compensate for chemotherapy-related hemoglobin reduction for small muscle mass exercise but are insufficient to maintain large muscle mass exercise (pulmonary VO(2)peak, leg press strength). The excess O(2) required to perform work, increased Pi:PCr ratio and myosteatosis together suggest suppressed fat oxidation during chemotherapy.