# Circadian clock and temporal control in nutrient metabolism

> **NIH NIH R01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2023 · $453,816

## Abstract

Project Summary
The circadian clock confers temporal control to metabolic pathways, and its disruption leads to insulin resistance
and obesity. Skeletal muscle plays a critical role in nutrient metabolism and protein homeostasis. We and others
demonstrated that the muscle-intrinsic clock regulates skeletal muscle development, growth, and metabolism.
Despite the extensive studies of circadian regulation in glucose and lipid metabolism, there is a current
knowledge gap regarding clock function in protein metabolism that determines muscle mass. In addition,
although circadian misalignment is prevalent in a modern lifestyle, potential circadian etiologies underlying
muscle wasting and impaired metabolic capacity remains unknown. We have identified a novel clock-driven
temporal control of PI3K-Akt-mTORC1 signaling in skeletal muscle that is independent of feeding-induced
activation. Surprisingly, clock disruption mimicking shiftwork resulted in progressive muscle atrophy
accompanied with impaired PI3K-Akt signaling and elevated protein turnover. Furthermore, mechanistic studies
revealed circadian clock transcriptional control of the Insulin/Igf-1-PI3K-Akt-mTOR signaling cascade. These
findings, together with prior research support a hypothesis that that the muscle-intrinsic clock confers temporal
control in PI3K-Akt-mTOR cascade to drive protein metabolism and insulin sensitivity, and this mechanism
underlies circadian disruption-induced muscle atrophy and insulin resistance. The overarching goal of this project
is to comprehensively define this newly discovered clock-PI3K-Akt-mTOR regulatory axis in muscle nutrient
homeostasis and muscle mass regulation. Specifically, we will leverage our unique clock modulation models with
multi-omics approaches to comprehensively define the molecular mechanisms responsible for and the
physiological significance of the clock-Akt-mTOR regulatory axis in protein metabolism, insulin sensitivity and
muscle mass maintenance. More importantly, we propose to test genetic and pharmacological clock-augmenting
interventions to counteract muscle anabolic and metabolic deficits induced by clock disruption. The outcome of
this proposal may uncover a circadian etiology underlying impaired metabolic capacity in sarcopenia and provide
the mechanistic basis for clock-targeting interventions.

## Key facts

- **NIH application ID:** 10754101
- **Project number:** 1R01DK137515-01
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** Ke Ma
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $453,816
- **Award type:** 1
- **Project period:** 2023-09-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10754101

## Citation

> US National Institutes of Health, RePORTER application 10754101, Circadian clock and temporal control in nutrient metabolism (1R01DK137515-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10754101. Licensed CC0.

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