764A Poster - 12. Physiology, metabolism and aging
Thursday April 07, 2:00 PM - 4:00 PM

Authors:
Yiming Guo ¹; Christopher Livelo ¹; Shweta Varshney ²; Farah Abou Daya ¹; Hiep Le ³; Satchidananda Panda ³; Girish Melkani ^1,2

Affiliations:
1) Department of Pathology, Division of Molecular and Cellular Pathology, School of Medicine, The University of Alabama at Birmingham, AL 35294, USA; 2) Department of Biology and Molecular Biology Institute, San Diego State University San Diego, CA 92182, USA; 3) Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

Keywords:
f. dietary restriction/fasting; k. circadian rhythms and sleep

Pathological obesity due to genetic predisposition affects countless people globally and leads to several ailments such as cardiovascular disease, metabolic syndrome and impaired muscle function. Our lab has developed a novel genetic-induced obesity model using Drosophila melanogaster which contains a sphingosine kinase 2 (Sk2) gene mutation. Sk2 mutation leads to accumulation of ceramide and eventually results in lipotoxicity which hampers muscle function and exhibits obese related metabolic parameters. Interestingly, by employing time-restricted feeding (TRF), an intervention which maintains isocaloric consumption that limits the daily feeding window from ZT0-ZT12, Drosophila melanogaster (fruit fly model) with genetic induced-obesity showed attenuated phenotypes. Flies under TRF improved skeletal muscle function, increased insulin sensitivity, reduced intramuscular lipid infiltration and preserved mitochondrial integrity compared to their ad libitum feeding (ALF) counterparts (Villanueva et al, 2019, Nature Communication). In this study, we explored the pathophysiological basis of TRF-mediated benefits utilizing transcriptomic data of indirect flight muscle (IFM). We investigated physiology using functional and genetic validations, cytological and biochemical approaches. We found flies under TRF intervention displayed significant upregulation of Gnmt, Sardh and CG5955, key players of S-adenosylmethionine regulation, and downregulation of Dgat2, a key gene for triglyceride synthesis. IFM-specific knock-down (KD) of Gnmt, Sardh and CG5955 led to progressive muscle dysfunction. Further, IFM-specific KD of Dgat2 retained muscle function during aging. In addition, genes associated with AMP kinase (AMPK) signaling, glycogen metabolism, glycolysis, tricarboxylic acid (TCA) cycle and electron transport chain (ETC) signaling were specifically upregulated in GIO model under TRF. Altogether, we identify the GIO-specific pathways in the regulation of muscle function under TRF, which emphasized the role of feeding-fasting rhythms on combating comorbidities linked with genetic obesity. Validation of these genes in obesity-induced skeletal muscle health and the role of circadian clock in that process is currently underway.