# Receptor-mediated glucose sensing and skeletal muscle function

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $390,000

## Abstract

PROJECT SUMMARY
Skeletal muscle is central to the development of metabolic dysfunction during type 2 diabetes (T2D) and
obesity. In addition, these conditions are often accompanied by accelerated muscle loss despite the presence
of nutrient excess. This suggests uncoupling of nutrient sensing mechanisms with the molecular pathways that
control muscle plasticity. For instance, depletion of intramuscular nicotinamide adenine dinucleotide (NAD) is
linked to skeletal muscle loss and dysfunction, while strategies that restore or increase its levels can reverse
this pathogenesis. Particularly, genetic or pharmacological inhibition of poly(ADP-ribose) polymerases 1
(PARP1), a major NAD consumer, improves muscle fitness through increases in NAD availability and the
activation of NAD-dependent deacetylase sirtuin-1 (SIRT1). Thus, identifying physiological pathways that link
energy metabolism to the regulation of PARP1 activity can lead to the development of innovative therapies for
the prevention or treatment of muscle degeneration and metabolic dysfunction. Preliminary data suggest that
direct sensing of circulating glucose by sweet taste receptors (STRs) regulates PARP1 activity to control the
adaptive potential of skeletal muscle. Specifically, whole body or skeletal muscle-specific deletion of T1r2 gene
of STRs (T1R2-KO) enhances mitochondrial function, oxidative capacity, exercise tolerance, and induces mild
increases in myofiber size. These improvements are linked to attenuated PARP1 activity, increased NAD pool,
and enhanced glucose utilization towards nucleotide biosynthesis. Consequently, T1R2-KO mice are protected
from metabolic derangements associated with diet-induced obesity, including muscle mass loss. Thus, it was
hypothesized that the T1R2 receptor is a constitutive sensor of glucose availability to adjust intracellular
pathways that control the metabolic basis of skeletal muscle plasticity. This hypothesis is tested through
comprehensive studies using mice with constitutive or inducible muscle-specific deletion of the T1r2 gene to: 1)
Elucidate the role of T1R2 signaling network in the regulation of muscle bioenergetics and function.
Specifically, a) probe signaling pathway leading to PARP1 regulation and NAD bioavailability, b) identify
downstream effectors of NAD-dependent activation of SIRT1 and 2, c) assess contributions of STRs in the
regulation of substrate utilization, and d) determine interactions between STR signaling and established
intracellular energy sensors (i.e. AMPK, mTORC1, Akt). 2) Investigate contributions of T1R2-mediated glucose
sensing in the regulation of muscle mass. Specifically, a) assess physiological effects of inducible deletion of
STR signaling in adult skeletal muscle to mimic longitudinal effects of pharmacological treatments targeting
STRs, b) define contributions of STR signaling to muscle mass adaptations in response to treatments that
induce muscle hypertrophy or atrophy, c) spatiotemporal expression of...

## Key facts

- **NIH application ID:** 10095313
- **Project number:** 1R01DK127444-01
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** George Kyriazis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $390,000
- **Award type:** 1
- **Project period:** 2021-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10095313

## Citation

> US National Institutes of Health, RePORTER application 10095313, Receptor-mediated glucose sensing and skeletal muscle function (1R01DK127444-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10095313. Licensed CC0.

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