# Novel molecular mechanisms of skeletal muscle insulin resistance in physically inactive older adults

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $171,360

## Abstract

Abstract
The over-65 population is not only increasing at an alarming rate, but because six out of 10 will be managing
more than one chronic condition by 2030, they will make up a much greater proportion of hospitalizations than
ever before. Hospitalizations for disease, injury, and/or surgery in this group are likely to impair physical
mobility and, therefore, the older adults capacity to be physically active both during hospitalization and beyond.
The resulting sedentary lifestyle is likely to be accepted as the “new normal”, ultimately increasing the risk of
skeletal muscle and metabolic dysfunction (e.g. impaired glucose disposal, insulin resistance). These
devastating outcomes are neither inevitable nor necessary if prevented with an appropriate mechanism-based
intervention.
A novel mechanism that may contribute to physical inactivity-induced insulin resistance is accumulation of
inflammation and ceramide within skeletal muscle initiated by activation of the toll-like receptor 4
(TLR4)/MyD88 signaling pathway. We have previously shown that skeletal muscle TLR4/MyD88 signaling
regulates pro-inflammatory pathways and ceramide biosynthesis whereas knockdown of TLR4 protects muscle
against lipid-induced insulin resistance. Of interest, increased skeletal muscle TLR4, inflammation and
ceramide has been tied to various metabolic disturbances such as diabetes and insulin resistance. However, it
is currently unknown if skeletal muscle TLR4/MyD88 signaling and the subsequent increase in inflammation
and ceramide are a key mechanism associated with insulin resistance due to physical inactivity in older adults.
Dr. Drummond’s preliminary work supports the hypothesis that physical inactivity increases TLR4,
inflammation, and ceramide biosynthesis in skeletal muscle of older adults. Additionally, our preliminary data in
mouse experiments indicate that hyperactive MyD88 signaling regulates insulin resistance caused by short-
term physical inactivity. Therefore, Dr. Drummond and his multidisciplinary research team have proposed to
conduct parallel clinical studies in older adults and a series of mechanistic studies using muscle-specific
mouse models and drug intervention studies to test whether skeletal muscle TLR4/MyD88 signaling is
important in the production of inflammation and ceramide and therefore insulin resistance caused by physical
inactivity. These findings will be foundational for developing treatments to prevent insulin resistance in inactive
older adults.

## Key facts

- **NIH application ID:** 10225731
- **Project number:** 3R01AG050781-05S1
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Micah J Drummond
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $171,360
- **Award type:** 3
- **Project period:** 2016-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10225731

## Citation

> US National Institutes of Health, RePORTER application 10225731, Novel molecular mechanisms of skeletal muscle insulin resistance in physically inactive older adults (3R01AG050781-05S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10225731. Licensed CC0.

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