The loss of skeletal muscle function occurs with age but the reason why there are differences in the rate and magnitude of loss between females and males is not clear. Losses in women are likely related to changes in ovarian hormones in addition to aging but mechanistic effects of these hormones on skeletal muscle have not been elucidated. The overall goal of the studies outlined in this application is to determine hormone-mediated mechanisms that contribute to muscle strength loss in aged females. Estradiol is the crucial ovarian hormone that affects the function of the key contractile protein, myosin, which in turn affects muscle strength in young adult female mice but estradiol's effects on muscle in aged female mice are unknown. Thus, the first aim of this application is to determine the extent to which estradiol treatment improves myosin function and muscle strength in ovarian-failed, aged mice. Estradiol treatment will be evaluated in various models of estradiol deficiency so that any age-related differential effects of estradiol on myosin and muscle functions will be revealed. Extensive functional analyses will include voluntary muscle performance, maximal in vivo lower-leg muscle strength, contractile capacity of isolated muscles, and molecular structure-function analyses of myosin.
The second aim of this application is to determine if estradiol is beneficial to myosin and muscle strength independent of the physical activity level. The direct effects of estradiol on skeletal muscle are imperative to determine because the loss of and treatment with estradiol occurs systemically and as such, non-muscle tissue is affected and could influence muscle through indirect mechanisms. For example, physical activity of rodents is influenced by estradiol status and could indirectly impact muscle strength.
The third aim of this application is to test the hypothesis that the beneficial effects of estradiol on myosin and muscle function are mediated by nuclear estrogen receptors, which regulate oxidative stress-related genes. To accomplish this, estrogen receptors will be blocked and it is predicted that this pharmacological intervention will negate all of estradiol's beneficial effects on myosin and muscle. Next, a panel of genes that are related to oxidative stress and antioxidant defense systems in estradiol-deficient and estradiol-replete mice will be probed. The rationale behind this is that myosin is susceptible to oxidation and that several oxidative stress-related genes are modulated by estradiol in non-muscle tissues. At the conclusion of these studies we will know the extent to which age-related estradiol deficiency causes a decline in muscle strength due to decrements in myosin function and whether estradiol treatment reverses these declines through genomic mechanisms. The long-term objective of our research is to elucidate the overall mechanisms underlying age- and hormone-related skeletal muscle functional losses and to utilize this knowledge to devise optimal strategies for preventing, reversing, or at least slowing the progression of weakness that occurs with age. Skeletal muscle weakness is a significant health concern because it directly contributes to a decreased qualit of life, particularly for older women.

Public Health Relevance

Aging results in muscle weakness that impacts the quality of life of older adults. The research described in this application will determine how estradiol treatment can benefit estrogen-deficient females by improving muscle strength.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG031743-04
Application #
8220749
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Williams, John
Project Start
2009-02-01
Project End
2014-01-31
Budget Start
2012-02-15
Budget End
2013-01-31
Support Year
4
Fiscal Year
2012
Total Cost
$284,499
Indirect Cost
$80,153
Name
University of Minnesota Twin Cities
Department
Physical Medicine & Rehab
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Cabelka, Christine A; Baumann, Cory W; Collins, Brittany C et al. (2018) Effects of ovarian hormones and estrogen receptor ? on physical activity and skeletal muscle fatigue in female mice. Exp Gerontol :
Torres, Maria J; Kew, Kim A; Ryan, Terence E et al. (2018) 17?-Estradiol Directly Lowers Mitochondrial Membrane Microviscosity and Improves Bioenergetic Function in Skeletal Muscle. Cell Metab 27:167-179.e7
Levy, Yotam; Ross, Jacob A; Niglas, Marili et al. (2018) Prelamin A causes aberrant myonuclear arrangement and results in muscle fiber weakness. JCI Insight 3:
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Houang, Evelyne M; Haman, Karen J; Kim, Mihee et al. (2017) Chemical End Group Modified Diblock Copolymers Elucidate Anchor and Chain Mechanism of Membrane Stabilization. Mol Pharm 14:2333-2339
Laakkonen, Eija K; Kulmala, Janne; Aukee, Pauliina et al. (2017) Female reproductive factors are associated with objectively measured physical activity in middle-aged women. PLoS One 12:e0172054
Bosnakovski, Darko; Chan, Sunny S K; Recht, Olivia O et al. (2017) Muscle pathology from stochastic low level DUX4 expression in an FSHD mouse model. Nat Commun 8:550
Valencia, Ana P; Schappal, Anna E; Morris, E Matthew et al. (2016) The presence of the ovary prevents hepatic mitochondrial oxidative stress in young and aged female mice through glutathione peroxidase 1. Exp Gerontol 73:14-22
Dandapat, Abhijit; Perrin, Benjamin J; Cabelka, Christine et al. (2016) High Frequency Hearing Loss and Hyperactivity in DUX4 Transgenic Mice. PLoS One 11:e0151467

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