Muscle Dysfunction in Androgen Deprivation: Role of Ryanodine Receptor.

摘要

Lowering androgen levels by orchiectomy (ORX) or reversible pharmacological treatment is a key therapeutic goal in prostate cancer patients. This life prolonging treatment is accompanied by the adverse side effects of increased adiposity, loss of muscle mass, and osteoporosis that negatively affect quality of life. Thus, there is a need for therapeutic agents that improve the quality of life for prostate cancer patients treated with androgen deprivation therapy (ADT). We hypothesize that mice undergoing ORX have reduced muscle specific force due to calcium leak through RyR1, which is caused by high levels of TGF-beta released from the bone during ADT-related bone loss. We studied the effect of ORX in young and aged mice over a period of 20 weeks after surgery. We found that ORX mice had decreased muscle weight, mid-calf cross-sectional area, forelimb grip strength, and bone mineral density (BMD), and increased total body fat content. However, muscle specific force was not decreased in ORX mice compared to sham operated mice. In future experiments adult mice will be treated with ORX and/or androgen receptor antagonist, to better mirror the clinical approach in prostate cancer patients. Because in our experiments the lowest level of BMD was reached at 4 weeks after ORX, we will measure muscle specific force at 4 weeks and 8 weeks after surgery to determine if an early calcium leak could be causing long-term effects, such as decreased muscle mass, body weight and forelimb grip strength.