# Mechanism through which chronically elevated mTOR activity impairs aged muscle recovery after disuse atrophy

> **NIH VA I01** · OKLAHOMA CITY VA MEDICAL CENTER · 2024 · —

## Abstract

SUMMARY
Older Veterans have a higher burden of comorbid chronic diseases compared to the general population, resulting
in more frequent inpatient hospitalizations. A consequence of frequent and recurring hospitalizations is the
acceleration of age-related loss of skeletal muscle mass and strength (sarcopenia). The combined effect of
sarcopenia and hospitalization exacerbates muscle dysfunction since older adults do not adequately recover
from bedrest placing them on an accelerated trajectory toward loss of independence. Therefore, the period
around hospitalization is a critical period to intervene to prevent disability, loss of independence, and frailty in
Veterans. It is not clear why skeletal muscle in older individuals is resistant to regrowth after a period of atrophy.
Further, current strategies to enhance regrowth in older skeletal muscle remain largely ineffective. The proposed
work is significant because it provides evidence that mTOR activation is the cause, not the solution, to the failure
to recover muscle after disuse. The current proposal is innovative in that it goes against current therapies that
were based on data from young animals; it proposes three independent but overlapping mechanisms; and it
uses sophisticated combined isotope labeling and proteomic approaches to study the periods around disuse
atrophy. The overall hypothesis of this proposal is that that chronically activated mTOR in aged skeletal muscle
impairs the recovery of muscle mass/function after a period of disuse. To test this overall hypothesis, we will use
old (28 mo) F344/BN rats with and without an mTOR inhibitor (rapamycin (Rapa)) to address three specific aims
that determine if inhibiting chronic mTOR activity in older muscle: 1) corrects the mitochondrial dysfunction that
impairs muscle recovery after a period of HU, 2) improves the proteostatic stress that impairs muscle recovery
after a period of HU, and 3) helps resolve fibrosis that impairs muscle recovery after a period of HU. Our
hypotheses are that suppression of chronically active mTOR activity will: 1) increase the selective translation of
mRNA to improve mitochondrial protein remodeling, improve the deterioration of network connectivity, and
improve mitochondrial function, 2) improve proteostatic maintenance during RE, and 3) reduce muscle fibrosis
to improve mechanotransduction during RE. For these specific aims we will use our innovative targeted and
discovery-based kinetic proteomics along with novel (e.g. mitochondrial imaging) and well-established
secondary outcomes, including functional outcomes, to support our proteomic outcomes. It is hoped that these
experiments will clarify the underlying cause of failed recovery in muscle of older Veterans, and whether we
should fundamentally change the approach to enhance recovery after disuse in aged muscle. This knowledge
could help prevent the accelerated progression to a disability threshold for a significant number of older Veterans.

## Key facts

- **NIH application ID:** 10871826
- **Project number:** 5I01BX005592-03
- **Recipient organization:** OKLAHOMA CITY VA MEDICAL CENTER
- **Principal Investigator:** Benjamin Francis Miller
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10871826

## Citation

> US National Institutes of Health, RePORTER application 10871826, Mechanism through which chronically elevated mTOR activity impairs aged muscle recovery after disuse atrophy (5I01BX005592-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10871826. Licensed CC0.

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