Utilizing senolytics to enhance the response to exercise in cachectic mice - Project Summary. Skeletal muscle mass and function are key determinants of an individual’s healthspan and are tightly correlated with both physical and metabolic health. In cancer survivors, the loss of muscle mass that occurs following cancer, termed cancer cachexia, is a major contributor to mortality, as well as reduced quality of life during and after the disease. Unfortunately, one of the most extensively used treatments for cancer patients, chemotherapy, is almost as bad as the cancer itself due the negative effects that chemotherapy has on healthy cells. Chemotherapy treatments such as cisplatin, induce DNA damage, thereby compounding an already deleterious process in healthy tissues and cells. Severe or unrepaired DNA-damage causes cell death and tissue atrophy, in addition to being a major inducer of cellular senescence. Recent work by our lab has linked an accumulation of senescent cells as a novel contributing factor to cisplatin-mediated loss of muscle mass and function. In response to cisplatin, there is an accumulation of senescent cells in muscle, which is correlated to a reduction in muscle fiber cross-sectional area. Considering senescent cells have been linked to sarcopenia, removal of these senescent cells using senescent cell killing compounds, senolytics, could help slow muscle loss during cisplatin treatment. Exercise training is the most effective way to increase skeletal muscle mass, in addition to improving physical function and whole-body metabolism. Following chemotherapy treatment, the response to exercise is attenuated (termed anabolic resistance), and individuals treated with chemotherapy following surgery have a blunted response to exercise compared with surgery alone. Given that elimination of senescent cells augments muscle growth and regeneration in old mice, senolytics could serve as a novel therapeutic intervention to not only delay cisplatin-induced atrophy but also improve the response to exercise training. Our central hypothesis is that cisplatin-treated mice receiving senolytics will experience less atrophy and an augmented response to exercise when compared to controls. We will utilize the plant-based flavonoids, fisetin and quercetin (F+Q), as our senolytic cocktail. In addition to their excellent senolytics properties, F+Q exert many other beneficial effects, such as antioxidant and anti-inflammatory, and promoting mitochondrial biogenesis. To address our hypothesis, we will pursue three specific aims: 1) delete senescent cells in mice treated with F+Q to determine if cellular senescence mediates cisplatin-induced muscle atrophy, 2) examine senescent cells as contributors to anabolic resistance following progressive weighted wheel running, and 3) characterize the cellular landscape and identify the molecular signature of muscle senescent cells. We will utilize an age-appropriate mouse model to identify the therapeutic potential of senescent cells to slow both the physical and metabolic aspects of chemotherapy-induced cachexia and anabolic resistance. If our hypothesis is correct, the results from our proposed studies could influence the treatment of cachexia and associated metabolic derangement, thereby creating new interventions and therapeutic strategies.
