The aging population is rapidly expanding in our society, and sarcopenia contributes to physical frailty and cardiometabolic risks in elderly people. The age-related declines in muscle strength and mitochondrial function cannot be entirely explained by the respective decreases in muscle mass and mitochondrial content. We propose that these disproportionate effects are related to altered protein homeostasis. Increased oxidative damage to proteins and DNA occurs with age, and reduced muscle protein turnover and consequent accumulation of deleterious post-translational modifications may explain these results. We developed a novel method to determine the relative abundance of """"""""old"""""""" (those synthesized earlier) to """"""""new"""""""" (newly synthesized) proteins in specific protein pools. Using 2-dimensional gel electrophoresis, we observe trains of gel spots (gel spot isoforms) of the same protein. Gel spot isoforms correspond to the separation of a protein that has undergone modifications altering the isoelectric pH (pl) without substantially shifting its mass. Following in vivo metabolic labeling of proteins with a stable isotope of phenylalanine, different gel spot isoforms of an individual protein have widely variable isotopic enrichment. We find that a gel spot isoforms with greater modifications (e.g.;oxidation) also exhibit lower isotopic enrichment, indicating that these proteins were formed largely before the isotope infusion. We will determine if the relative accumulation of """"""""old"""""""" and damaged proteins is higher in older people and if aerobic exercise training can accelerate the removal of old proteins and replacement with newly synthesized proteins by increasing protein synthesis and degradation. Since type II fiber atrophy occurs with age, we will determine whether synthesis rates of myosin heavy chain (MHC) isoforms IIa and IIx are altered with old age. We will also determine the effect of aerobic vs. resistance exercise training on synthesis rates of individual MHC isoforms and whether age affects the response to specific exercise programs. We will also contrast the effects of aerobic vs. resistance training on accumulation of old, modified proteins. The hypothesis is that aerobic exercise will replace damaged and old proteins with newly synthesized proteins whereas resistance exercise increases synthesis of specific contractile proteins with effect on replacing old and modified proteins. We will determine whether a combined exercise program increases synthesis of specific contractile proteins as well as removal of old and modified proteins. Additional mechanistic studies are planned to determine the relative impact of reactive oxygen species production and antioxidant defense system on protein modification. The proposed studies will for the first time determine whether age increases the relative composition of old and damaged isoforms of mitochondrial, myofibrillar, and sarcoplasmic proteins and a novel mechanism by which exercise programs correct the abnormality. The proposed studies will apply novel and innovative methodologies developed in our laboratory to address important mechanistic questions that may reveal potential therapeutic targets to combat sarcopenia.

Public Health Relevance

In this ongoing research project we propose to understand the cause of age-related muscle wasting and weakness which is a major cause of frailty and morbidity of the rapidly expanding aging population. Seminal methodological advances in our laboratory will be applied to determine whether alterations in homeostasis of proteins, the molecules responsible for muscle functions could cause muscle change in elderly people. Understanding the cause of muscle weakness could pave the way for preventive and therapeutic strategies to help maintain or improve quality of life with advanced age.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG009531-21
Application #
8717542
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Dutta, Chhanda
Project Start
1993-04-15
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
21
Fiscal Year
2014
Total Cost
$682,432
Indirect Cost
$249,691
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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Walrand, Stephane; Short, Kevin R; Heemstra, Lydia A et al. (2014) Altered regulation of energy homeostasis in older rats in response to thyroid hormone administration. FASEB J 28:1499-510
Johnson, Matthew L; Robinson, Matthew M; Nair, K Sreekumaran (2013) Skeletal muscle aging and the mitochondrion. Trends Endocrinol Metab 24:247-56

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