Ryanodine receptor 1 remodeling in cancer-associated muscle dysfunction
Muscle weakness is common in advanced cancers and is a cause of significant cancer-related morbidity and mortality. The mechanisms of cancer-associated muscle dysfunction are unknown and no effective treatment exists. Ryanodine receptor 1 (RyR1) is the skeletal muscle sarcoplasmic reticulum Ca2+ release channel required for excitation-contraction coupling. RyR1 remodeling via oxidative stress results in leaky channels and poor muscle function. We have found that mice with breast cancer bone metastases exhibit significant muscle dysfunction due to leaky RyR1 channels. Targeted therapy against leaky RyR1 channels (Rycals) improve muscle function and may be an effective therapy for cancer-associated muscle weakness.