Muscle Circadian Clock Disruption as a Cancer Cachexia Modifier

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY/ABSTRACT Cancer Cachexia (CC) presents a profound challenge to cancer survival, affecting roughly 80% of cancer patients and contributing to a substantial proportion of cancer-related fatalities. Among its manifestations, skeletal muscle weakness and wasting stand as a pivotal concern, impacting both the quality of life and survival rates of afflicted individuals. The goal of this F32 application is to pursue research training in the newly emerging area of muscle circadian clock disruption in cancer The circadian clock mechanism in skeletal muscle regulates a rhythmic daily program of gene expression (i.e. clock output genes) contributing to muscle homeostasis, while muscle clock disarrangements are implicated in several models of muscle atrophy. My preliminary investigations unveiled transcriptomic shifts in core clock genes within skeletal muscle in various pre-clinical CC models, suggesting a potential role for the clock in cancer-induced muscle detriments. These observations are supported by compelling unpublished data from collaborative research between the Esser and Judge laboratories, showing disruptive alterations in the muscle circadian clock and clock output genes in pancreatic cancer-bearing mice. These combined findings provide the rationale for this F32 proposal. This proposal stands out for its scientific novelty, being the first to delineate the muscle clock profile and assess its impact as a modifier in the development and progression of CC. My overarching hypothesis is that the muscle clock serves as a CC modifier and loss of clock function will lead to accelerated and aggravate CC-induced muscle impairments. The outcomes of this proposal will 1) define the cachexia stage at which the muscle clock is disrupted, interrogate clock disruptions and its relationship with cachexia manifestations in a muscle type-specific fashion, and 2) provide an extensive assessment of both behavioral and muscle-specific changes in CC modulated by the muscle clock mechanism.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Based on pre-clinical and clinical reports of circadian disruptions in cancer hosts in combination with our preliminary findings implicating muscle clocks to cachectic muscle, this project aims to investigate the role of the muscle circadian clock in Cancer Cachexia (CC) progression, a condition affecting muscle mass and function in up to 80% of cancer patients. Utilizing circadian reporter mice and inducible muscle-specific genetic models, the study will define stage and muscle-specific changes in the muscle clock during CC development and assess its contribution to disease onset and progression. By integrating expertise in circadian biology and CC research, this training opportunity not only advances the scientific understanding of cancer-induced muscle detriments, moving the field one step closer to accessible and effective therapeutics but also cultivates essential skills for my future research endeavors.