Enhancing Skeletal Muscle Recovery and Mitochondrial Function in Older Cancer Survivors - PROJECT SUMMARY/ABSTRACT Skeletal muscle dysfunction is a prevalent and debilitating problem in older adults with cancer. In cancer patients, this dysfunction can manifest as muscle weakness, muscle wasting, and muscle fatigue, leading to physical function impairment and increased risk of falls and fractures. Most of what we know about skeletal muscle dysfunction in oncology comes from studies on cancer cachexia, a wasting syndrome in patients with incurable metastatic disease. However, cancer survivors often experience accelerated muscle dysfunction independent of cachexia. The mechanisms underlying accelerated muscle dysfunction in survivors remain unknown. To address this, we propose a mechanistic ancillary study embedded within our ongoing, R01-funded, randomized clinical trial (PROFFi). The primary objective of PROFFi is to determine the effects of exercise and an oral senolytic therapy, given in combination and alone, on physical function (primary endpoint) in frail postmenopausal breast cancer survivors. Secondary endpoints include changes in clinical, functional, and blood-based markers of biological aging. We recognize, however, that an individual’s physical function is dependent on their skeletal muscle health and mitochondrial biogenesis. Furthermore, the impact of exercise and senolytics, interventions such as on our own, on skeletal muscle tissue and mitochondrial function are even less well understood. Hence, the proposed ancillary study aims to evaluate the effect of our interventions on muscle mass, strength, and mitochondrial function. We will test the hypothesis that targeting senescent cells with the combination of exercise and a senolytic therapy will lead to greater 1) improvements in muscle mass, strength, and function, and 2) enhancements in muscle mitochondrial respiration and genome integrity, compared to exercise alone, senolytic alone, or placebo. To test this, we will invite a subset of trial participants to complete additional muscle assessments (dynamometry, imaging) and skeletal muscle biopsies (mitochondrial respiration, genome integrity) pre- and post-intervention. We will also perform nanopore long-read RNA sequencing on muscle biopsy tissue to characterize gene expression patterns associated with muscle recovery and mitochondrial function. This study will unite a multidisciplinary team with expertise in cancer, aging, muscle and mitochondrial biology, radiology, exercise physiology, and biostatistics. Additionally, in response to PAR-24-289, this proposal leverages a critical window of opportunity to embed a mechanistic ancillary study within an ongoing cancer clinical trial, with established infrastructure, study population, and a rich dataset with clinical, functional, and biological aging- focused phenotyping. By integrating muscle and mitochondrial measures, this study will inform mechanism- based strategies to improve the musculoskeletal health of survivors, addressing a major public health issue and a priority of NIAMS. Moreover, given that accelerated skeletal muscle dysfunction affects many older adults without cancer, findings from this study would have a major positive impact that extends far beyond oncology.
