The loss of skeletal muscle strength is an undesirable consequence of aging and is predictive of falls and declining functional status leading to frailty, disability, and loss of independence for aged individuals. Skeletal muscle of females is additionally affected by age due to the reduction of ovarian hormone production with the onset of menopause. Estradiol is the key hormone because strength loss in females is prevented or reversed by treatment with this hormone. The long-term objective of our research is to elucidate the mechanisms underlying age- and estradiol-related skeletal muscle functional losses and to utilize this knowledge to devise optimal strategies for offsetting weakness that occurs with age. This is a competitive renewal submission of a funded proposal whereby exciting discoveries and numerous publications from the previous funding period have led to novel hypotheses that are outlined in this proposal. The overall focus of the project remains to be on how estradiol impacts skeletal muscle strength in aged females;the goals are to determine precise myosin- based mechanisms of strength loss in aging females and to elucidate how estradiol impacts the maintenance of muscle strength. Specifically, Aim 1 will test the hypothesis that aging and estradiol-deficiency affect the structure-function of myosin through estrogen receptor-mediated phosphorylation of contractile proteins. We propose that estradiol treatment increases phosphorylation of key contractile proteins such as the regulatory light chain to enhance force generation and to recruit myosin from a newly defined super-relaxed state, which possibly has wider implications in women's health because the super-relaxed state of myosin depresses metabolic rate of muscle and potentially whole body metabolism. The focus of the second aim is on maintenance of strength in females, which requires that muscle recover from the repeated bouts of injury that it sustains throughout life. As a consequence of estradiol deficiency, recovery of strength following muscle injury is incomplete.
Aim 2 will test the hypothesis that key mediators of early inflammation, specific chemokines/cytokines and their receptors recently found to be responsive to estradiol, significantly impact recovery of strength post-injury. Accomplishing these two aims will reveal underlying molecular mechanisms of muscle weakness in estradiol-deficient, aged females. Experimental approaches in each aim are combinatorial in nature, using in vitro and in vivo strategies and unique biophysical-physiological approaches to provide novel insights into how estradiol is beneficial for skeletal muscle of aged females. This work continues to challenge the concept that androgens are the only important sex hormones for muscle strength.

Public Health Relevance

Aging results in muscle weakness that impacts the quality of life of older adults. The research described in this proposal 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 #
2R01AG031743-06A1
Application #
8762119
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Williams, John
Project Start
2008-04-01
Project End
2019-04-30
Budget Start
2014-08-15
Budget End
2015-04-30
Support Year
6
Fiscal Year
2014
Total Cost
$395,931
Indirect Cost
$105,312
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:
O'Rourke, Allison R; Lindsay, Angus; Tarpey, Michael D et al. (2018) Impaired muscle relaxation and mitochondrial fission associated with genetic ablation of cytoplasmic actin isoforms. FEBS J 285:481-500
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
Wang, Hao; Alencar, Allan; Lin, Marina et al. (2016) Activation of GPR30 improves exercise capacity and skeletal muscle strength in senescent female Fischer344 × Brown Norway rats. Biochem Biophys Res Commun 475:81-6
Le, Gengyun; Lowe, Dawn A; Kyba, Michael (2016) Freeze Injury of the Tibialis Anterior Muscle. Methods Mol Biol 1460:33-41

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