765B Poster - 12. Physiology, metabolism and aging
Friday April 08, 2:00 PM - 4:00 PM

Authors:
Christopher Livelo ¹; Yiming Guo ¹; Shweta Varshney ²; Farah Abou Daya ¹; Hiep Le ²; Satchidananda Panda ²; Girish Melkani ¹

Affiliations:
1) University of Alabama at Birmingham School of Medicine; 2) Salk Institute for Biological studies

Keywords:
f. dietary restriction/fasting; p. metabolic disorders

Millions globally are affected by obesity stemming from a lifestyle of calorie-dense diets. Consequently, individuals afflicted with diet-induced obesity (DIO) incur complications including metabolic syndrome, cardiovascular disease, and compromised muscle function. In a previous study, we employed a time-restricted feeding (TRF) intervention, where daily feeding was limited to only the first 12 hours of the day in a Drosophila melanogaster model. Upon administration of a high-fat diet while under TRF, we observed improved skeletal muscle function compared to ad libitum feeding (ALF) counterparts in addition to improved metabolic parameters such as insulin sensitivity, mitochondrial integrity and body mass (Villanueva et al 2019, Nature communication). In this study, we evaluate the mechanistic basis of TRF-mediated benefits in DIO by utilizing muscle transcriptomic data of indirect flight muscle (IFM) followed by genetic validations, cytological and biochemical evidence. Interestingly, we found significant upregulation of glycine N methyltransferase (Gnmt), sarcosine dehydrogenase (Sardh) and CG5955, key players of one carbon-metabolism and S-adenosylmethionine regulation under TRF. We found downregulation of diacylglycerol o-acyltransferase 2 (Dgat2), a key gene for triglyceride synthesis. RNAi knockdown of the upregulated genes led to muscle dysfunction and abrogated TRF-mediated improvement of muscle performance. However, knockdown of Dgat2 preserved muscle performance during aging. Furthermore, de novo purine biosynthesis appeared to be upregulated and potentially led to increased ATP levels resulting in improved muscle performance. Folic acid, a key factor required in fueling the purine cycle was found to attenuate high-fat diet related muscle impairment. These findings contribute to potential mechanistic foundations that underlie TRF mediated improvement in muscle and provide a blueprint for pursuing therapy related research development relevant to obesity and muscle impairment.