# Molecular Mechanisms of  Exercise Benefits to Insulin Resistant People

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2022 · $602,339

## Abstract

PROJECT SUMMARY/ABSTRACT
Identification of the molecular regulatory points of exercise benefits is of high national priority because of the
opportunity to develop targeted novel therapeutics benefiting populations suffering from inactivity-related health
problems, including T2DM and pre-diabetes, characterized by insulin resistance (IR). IR is most prevalent in
the older population associated with sarcopenia. We propose novel metabolic regulatory role of PGC-1α4 (α4),
a hypertrophy gene, enhanced by resistance exercise (RE). Based on substantial preliminary data, we
hypothesize that α4, in cooperation with PPARβ (Rβ), promotes muscle glycolysis and insulin sensitivity (IS) as
well as increasing muscle mass and performance. Based on our novel preliminary data we will also investigate
whether by deacetylation of glycolytic proteins, RE enhances muscle glycolytic capacity. Rβ also reduces
oxidative stress that not only enhances IS but also contributes to other health benefits. New mRNA based data
indicates that RE reduces protein degradation which will be investigated in the current proposal. We will
determine whether 3 months of RE training enhances insulin sensitivity and muscle performance and mass in
IR people through pathways of enhanced glycolysis, deacetylation of glycolytic proteins reducing protein
degradation and enhancing synthesis and ameliorating oxidative stress. We will study 48 IR people 50-75 yrs
before and after 3 months of either 4-times/week resistance training or sedentary life and compare them with
lean IS people. We will collect vastus lateralis muscle biopsy samples before and after an acute exercise bout
and following a mixed meal to measure markers of glycolysis, energy metabolites, glycogen synthase,
glycogen content, α4, Rβ, insulin signaling proteins and proteome analysis. We will also measure markers of
oxidative stress including 8-OXO-dg (measure of DNA damage), oxidative damage to proteins and subsequent
muscle protein degradation, which we hypothesize is reduced by increased anti-oxidant effect of Rβ with RE
training. We also will use in vivo labeling of specific muscle proteins utilizing stable isotope labeled tracers to
determine whether α4 induced muscle hypertrophy occurs not only by reducing degradation but also by
enhancing contractile protein synthesis. Although our preliminary cell line studies provide supporting data on
direct effects of α4 and Rβ on IS and glycolysis and on the anti-oxidant effect of Rβ, direct effects of these
genes on our outcomes cannot be obtained in humans. Therefore we will perform studies in a mouse model
with high-fat diet-induced IR to show that α4 enhances IS and glycolysis and Rβ reduces oxidative stress. We
also will silence α4 and Rβ of mouse muscle to confirm our cell based results showing that contraction-induced
changes are dependent on α4 and Rβ. Together these human and animal studies will render the necessary
mechanistic explanation on how RE enhances IS, glycolysis, redu...

## Key facts

- **NIH application ID:** 10417138
- **Project number:** 5R01AG062859-04
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** K Sreekumaran Nair
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $602,339
- **Award type:** 5
- **Project period:** 2019-09-30 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10417138

## Citation

> US National Institutes of Health, RePORTER application 10417138, Molecular Mechanisms of  Exercise Benefits to Insulin Resistant People (5R01AG062859-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10417138. Licensed CC0.

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