The TAS1R2 G-protein-coupled receptor is an ambient glucose sensor in skeletal muscle that regulates NAD homeostasis and mitochondrial capacity

Joan Serrano, Jordan Boyd, Ian S. Brown, Carter Mason, Kathleen R. Smith, Katalin Karolyi, Santosh K. Maurya, Nishita N. Meshram, Vanida Serna, Grace M. Link, Stephen J. Gardell and George A. Kyriazis ()
Additional contact information
Joan Serrano: The Ohio State University; Columbus
Jordan Boyd: The Ohio State University; Columbus
Ian S. Brown: The Ohio State University; Columbus
Carter Mason: The Ohio State University; Columbus
Kathleen R. Smith: The Ohio State University; Columbus
Katalin Karolyi: The Ohio State University; Columbus
Santosh K. Maurya: The Ohio State University; Columbus
Nishita N. Meshram: The Ohio State University; Columbus
Vanida Serna: The Ohio State University; Columbus
Grace M. Link: The Ohio State University; Columbus
Stephen J. Gardell: Advent Health
George A. Kyriazis: The Ohio State University; Columbus

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract The bioavailability of nicotinamide adenine dinucleotide (NAD) is vital for skeletal muscle health, yet the mechanisms or signals regulating NAD homeostasis remain unclear. Here, we uncover a pathway connecting peripheral glucose sensing to the modulation of muscle NAD through TAS1R2, the sugar-sensing G protein-coupled receptor (GPCR) initially identified in taste perception. Muscle TAS1R2 receptor stimulation by glucose and other agonists induces ERK1/2-dependent phosphorylation and activation of poly(ADP-ribose) polymerase1 (PARP1), a major NAD consumer in skeletal muscle. Consequently, muscle-specific deletion of TAS1R2 (mKO) in male mice suppresses PARP1 activity, elevating NAD levels and enhancing mitochondrial capacity and running endurance. Plasma glucose levels negatively correlate with muscle NAD, and TAS1R2 receptor deficiency enhances NAD responses across the glycemic range, implicating TAS1R2 as a peripheral energy surveyor. These findings underscore the role of GPCR signaling in NAD regulation and propose TAS1R2 as a potential therapeutic target for maintaining muscle health.

Date: 2024
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DOI: 10.1038/s41467-024-49100-8

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