Grant Abstract: Post-transcriptional Regulation of Satellite Cell Function

Grant Number: 5R00AR066696-05
PI Name: Doles
Project Title: Post-transcriptional Regulation of Satellite Cell Function

Abstract: Muscle wasting is a devastating condition that affects many elderly individuals and those with chronic disease. Numerous studies point to a direct relationship between muscle wasting and patient outcomes, including mortality, morbidity, response to chemotherapy, and surgical prognosis. Despite decades of extensive preclinical/ clinical research, therapeutic options for muscle wasting are limited. This can be attributed to a lack of understanding of the underlying pathological mechanisms of this etiologically complex condition. Our goal is to understand fundamental mechanisms of muscle wasting, particularly how muscle stem cell (or satellite cell) signaling/behavior is altered during this process. We recently identified several wasting-associated metabolites that regulate the satellite cell pool, thus potentially interfering with skeletal muscle maintenance and regeneration. We show that satellite cell activation is associated with widespread metabolic changes and that satellite cell behavior can be modified by ectopic metabolite exposure in vitro. Importantly, these potentially muscle-altering metabolites are components of many commercially available dietary supplements. While these metabolites are generally considered safe for human consumption, little is known about how ectopic metabolite exposure affects target cells, particularly stem cells. Based upon these preliminary findings, the main goal of the proposed research is to define the mechanisms of action of alpha-ketoglutarate and succinate on muscle stem cells. We propose two specific aims to address this central goal. The first aim will dissect two known cellular targets of these metabolites, the mitochondria and histone-modifying enzymes. The second aim will establish the muscle stem cell response to these orally administered metabolites and will begin to characterize cellular metabolome alterations associated with these functional stem cell changes. Overall, we expect that these studies will reveal critical insight into how metabolites influence muscle stem cell signaling and behavior and will be an important step towards integrating metabolic cues into therapies designed to target muscle wasting.

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