# Enhanced skeletal muscle proteostasis as a determinant of CNS protein quality control and neural function in the aging brain

> **NIH NIH RF1** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $53,514

## Abstract

PARENT PROJECT ABSTRACT
Proteostasis is essential for cell health and viability, and involves complex and highly conserved networks that
regulate protein translation, protein folding, and protein degradation. A decline in proteostasis function is one of
the features of aging tissues, particularly of the central nervous system (CNS). Indeed, the aging brain is
particularly sensitive to proteotoxic stress, as demonstrated by the high number of age-associated
neurodegenerative disorders characterized by protein misfolding and aggregation, including Alzheimer’s
disease (AD). The regulation of non-cell autonomous proteostasis has recently arisen as a novel mechanism
for the modulation of systemic homeostasis in worms and flies, and is postulated to have important organismal
effects on metabolism and aging. However, to date, there are no studies addressing the existence and activity
of these pathways in mammals, and their potential effects on the aging brain.
Transcription Factor E-B (TFEB) is a powerful master transcription factor regulator of proteostasis, integrating
autophagy and bioenergetics. We recently derived transgenic mice that moderately overexpress TFEB in
skeletal muscle, and discovered that the resulting enhanced skeletal muscle proteostasis function can
significantly ameliorate proteotoxicity in the CNS and also improve cognition and memory in aging mice. In this
project, we will determine if enhanced skeletal muscle proteostasis is capable of promoting neuroprotection,
uncover the mechanistic basis for this effect, develop powerful new models for testing mitophagy/autophagy
activity in the aging CNS, and determine if soluble factors secreted by muscle (“myokines”) mediate the
beneficial CNS effects in conditional skeletal muscleexpressing TFEB transgenic mice. Identification of
pathways regulating cross-talk between skeletal muscle and CNS may yield targets with high therapeutic
potential for diseases of the aging CNS.

## Key facts

- **NIH application ID:** 10427660
- **Project number:** 3RF1AG057264-03S1
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Constanza Javiera Cortes
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $53,514
- **Award type:** 3
- **Project period:** 2017-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10427660

## Citation

> US National Institutes of Health, RePORTER application 10427660, Enhanced skeletal muscle proteostasis as a determinant of CNS protein quality control and neural function in the aging brain (3RF1AG057264-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10427660. Licensed CC0.

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