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Grant Abstract: Enhancing Adaptations to Exercise

Grant Number: 5R01AG054454-03
PI Name: Lanza
Project Title: Enhancing Adaptations to Exercise

Abstract: Our preliminary data implicates chronic inflammation as a factor that may lead to biochemical abnormalities in muscle and attenuate some of the adaptive responses to exercise in skeletal muscle of older adults. The objective of the parent R01 project is to evaluate a hypothesis that chronic inflammation originating from inflamed adipose tissue triggers inflammatory responses within skeletal muscle, leading to oxidative stress, reduced mitochondrial capacity, compromised muscle quality, functional and metabolic impairments, and attenuated adaptive responses to exercise in older adults. The objective of this administrative supplement is to leverage banked biospecimens from the parent R01 project to interrogate two emerging concepts in the field of skeletal muscle physiology and exercise responsiveness. This proposal will focus on how n-3 PUFAs influence: 1. Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in aging skeletal muscle 2. Abundance and polarization of macrophages and regulatory t-cells (T-regs) in aging skeletal muscle Aim 1 will determine the impact of n-3 PUFAs on ER stress and the UPR in aging skeletal muscle. ER stress and basal activation of the UPR (i.e., tonic UPR) will be evaluated in skeletal muscle samples from young and older adults before and after n-3 PUFA or placebo. We will also evaluate the extent to which a single bout of exercise activates the UPR pathway (adaptive UPR) in skeletal muscle and the effects of n-3 PUFAs on this activation. This will be accomplished by examining ER stress and UPR from transcriptional (qPCR), translational (western blotting), and post-translational perspectives (phosphorylation) in skeletal muscle samples. Aim 2 will determine the impact of n-3 PUFAs on immune cell populations in aging skeletal muscle. Immunohistochemical staining of macrophage populations and regulatory T-cells will be performed on formalin fixed skeletal muscle biopsy samples obtained before exercise, 3 hours post-exercise, and 48 hours post exercise. The objective is to determine how n-3 PUFAs influence immune cell populations in resting muscle as well as mobilization and polarization of immune cells following exercise. The contribution of the proposed research is expected to be a detailed of understanding how n-3 PUFAs influence two salient molecular pathways in skeletal muscle following exercise in older adults. The data generated will provide new fundamental understanding of how n-3 PUFAs influence exercise response in aging muscle, and set a foundation for a future studies to understanding how dietary n-3 PUFAs may help older adults maintain functional muscle mass and healthspan. The knowledge gained in the proposed study will have a positive impact because “exercise resistance” represents a significant barrier to the prevention and reversal of disease and disability in humans. Understanding the potential for n-3 PUFA supplementation in preserving skeletal muscle health in older adults, particularly those at risk for sarcopenia and related metabolic disorders, will have significant benefit since exercise non-responders have increased risk for disease and disability.

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