Time-restricted feeding promotes skeletal muscle function in diet- and genetic-induced obesity through shared and unique pathways

Abstract

\n Obesity caused by genetic predisposition, a lifestyle of calorie-dense diets and/or circadian disruption can result in complications including metabolic syndrome, cardiovascular disease, and compromised muscle function. By employing time-restricted feeding (TRF), where daily feeding was limited to 12 hours during the day, we observed improved skeletal muscle function compared to ad libitum feeding (ALF). This was observed in both diet-induced obesity (DIO) and genetic-induced obesity (GIO) in a Drosophila melanogaster (fruit fly) model. We evaluated the mechanistic basis of TRF-mediated benefits by utilizing muscle transcriptomic data of indirect flight muscle (IFM) followed by genetic validations, cytological and biochemical evidences. Significant upregulation of glycine N methyltransferase (Gnmt), sarcosine dehydrogenase (Sardh), CG5955 and downregulation of diacylglycerol o-acyltransferase 2 (Dgat2) were commonly induced by TRF intervention under both obese conditions. Moreover, genetic inhibition of Gnmt, Sardh and CG5955 leads to skeletal muscle dysfunction, aberrant lipid accumulation and loss of TRF-mediated benefits. However, skeletal muscle-specific knockdown (KD) of Dgat2 retained muscle function during aging, a result that mimics TRF-mediated benefits. Furthermore, de novo purine biosynthesis appeared to be upregulated specifically in the DIO model under TRF which led to increased ATP levels resulting in improved muscle performance. Additionally, 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. TRF mediated benefits in GIO via activation of AMPK, which led to increased ATP levels. Altogether, we identify the shared and distinct pathways in the regulation of muscle function under TRF, which may aid further research and alternative therapeutic avenues that focus on combating comorbidities linked with obesity.