Thanks to early detection and treatment, women can expect excellent survival after an initial diagnosis of breast cancer. However, widely-used treatments such as anthracycline chemotherapy (AC) incur significant morbidity and mortality via effects on skeletal and cardiac muscle. Cardiomyopathy affects 1 in 5 breast cancer survivors within 3 years of diagnosis and over half of breast cancer survivors develop symptoms attributable to skeletal muscle weakness. A key mechanism underlying these toxicities involves adverse effects in mitochondria on cardiolipin, an essential phospholipid that forms the inner mitochondrial membrane and supports ATP synthesis. Anthracyclines (AC) in particular bind cardiolipin, rendering it unavailable to support proteins involved with the electron transport chain. Disturbing mitochondrial cardiolipin reduces ATP production in both skeletal and cardiac muscle. However, there has been no study to date in breast cancer patients showing that decreased cardiolipin levels are associated with the decline of structure and function of skeletal and cardiac muscle also diminishes from chemotherapy treatment. Our team has generated ground-breaking preliminary data in breast cancer survivors showing that cardiolipin levels, via a novel and robust assay in peripheral blood lymphocytes, predict reduced muscle mass in breast cancer survivors. We have also implemented direct measurement of cardiac function and structure using cardiac magnetic resonance (CMR) imaging and assessment of mitochondrial function in skeletal muscle using the well-established technique of 31-phosphorus magnetic resonance spectroscopy (31P-MRS). We recently completed a prospective study using cardiac strain measurement, a highly sensitive magnetic resonance-based biomarker of subclinical cardiac dysfunction, showing early decline in LV strain after anthracycline chemotherapy in breast cancer patients. We also have the ability to analyze cardiolipin profiles and lipids important to cardiolipin function. We are now poised to conduct an essential study of skeletal and cardiac muscle integrated with careful clinical assessment in breast cancer survivors receiving AC towards a long-term goal of targeting cardiolipin to reduce morbidity and mortality.
Aim 1 : Measure the relationships among skeletal muscle, cardiac muscle and cardiolipin status in breast cancer survivors.
Aim 2 : Assess longitudinal chemotherapy-induced changes in cardiolipin composition, skeletal muscle and cardiac muscle.
Women increasingly survive breast cancer thanks to improved treatments. Some treatments like chemotherapy can damage muscle cells via effects on the energy-producing components of cells called mitochondria, leading to weakness and heart failure. This damage may be mediated via a component of mitochondria called cardiolipin; this work will study changes in cardiolipin, skeletal muscle and cardiac muscle in breast cancer survivors to support diet-based treatments designed to prevent muscle damage after chemotherapy.
