The immediate career goal of this candidate is to expedite the research being conducted in her recently- awarded R01 (AG AG031743). This research is focused on the interactive effects of aging and estradiol on skeletal muscle and myosin functions. The long-term career goals of this candidate are 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 muscle weakness that occurs with age. These goals will be facilitated by a K02 award as a result of the candidate being relieved of many teaching and service-related faculty responsibilities, thus allowing her to intensively focus on research. The environment for the candidate to be successful in attaining these goals is exceptional. Senior, well-established investigators involved with the Center on Aging, The Muscular Dystrophy Center, and the Powell Center for Women's Health provide a network of excellence at the University of Minnesota in areas of biological aging, muscle, and women's health issues, respectively. A K02 award will afford the candidate time to become more engaged in activities sponsored by these Centers which will complement and advance her research program. In addition, as this "new investigator" is building her research team, relief time provided by a K02 award will be utilized to enhance the training she can offer to post-doctoral fellows and graduate and undergraduate students in her laboratory, expand current and establish new collaborations, and submit additional grant applications. The overall objective of the research that will be conducted during this award is to determine hormone-mediated mechanisms that contribute to muscle strength loss in aged females. Strength losses in females 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. Thus, the first aim of the research is to determine the extent to which estradiol treatment improves myosin function and muscle strength in ovarian- failed, aged mice.
The second aim i s to show that estradiol is beneficial to myosin and muscle strength independent of physical activity.
The third aim of the research is to test the hypothesis that the beneficial effects of estradiol on myosin and muscle function are mediated by estrogen receptors which regulate oxidative stress-related genes. At the conclusion of this K02 award, the candidate expects to have established her research team as the leader in the area of aging and hormonal effects on muscle structure and function and to have contributed significantly to our understanding of estradiol deficiency in age-related muscle weakness.

Public Health Relevance

Aging and loss of estrogen result in muscle weakness that impacts the quality of life of older adults. The applicant will conduct research to 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 Scientist Development Award - Research (K02)
Project #
5K02AG036827-04
Application #
8528442
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Williams, John
Project Start
2010-09-30
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2013
Total Cost
$108,808
Indirect Cost
$8,060
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
Kosir, Allison M; Mader, Tara L; Greising, Angela G et al. (2015) Influence of ovarian hormones on strength loss in healthy and dystrophic female mice. Med Sci Sports Exerc 47:1177-87
Dandapat, Abhijit; Bosnakovski, Darko; Hartweck, Lynn M et al. (2014) Dominant lethal pathologies in male mice engineered to contain an X-linked DUX4 transgene. Cell Rep 8:1484-96
Mader, Tara L; Novotny, Susan A; Lin, Angela S et al. (2014) CCR2 elimination in mice results in larger and stronger tibial bones but bone loss is not attenuated following ovariectomy or muscle denervation. Calcif Tissue Int 95:457-66
Novotny, Susan A; Mader, Tara L; Greising, Angela G et al. (2014) Low intensity, high frequency vibration training to improve musculoskeletal function in a mouse model of Duchenne muscular dystrophy. PLoS One 9:e104339
Gordon, Bradley S; Lowe, Dawn A; Kostek, Matthew C (2014) Exercise increases utrophin protein expression in the mdx mouse model of Duchenne muscular dystrophy. Muscle Nerve 49:915-8
McKeehen, James N; Novotny, Susan A; Baltgalvis, Kristen A et al. (2013) Adaptations of mouse skeletal muscle to low-intensity vibration training. Med Sci Sports Exerc 45:1051-9
Call, Jarrod A; Warren, Gordon L; Verma, Mayank et al. (2013) Acute failure of action potential conduction in mdx muscle reveals new mechanism of contraction-induced force loss. J Physiol 591:3765-76
Novotny, S A; Warren, G L; Lin, A S et al. (2012) Prednisolone treatment and restricted physical activity further compromise bone of mdx mice. J Musculoskelet Neuronal Interact 12:16-23
Baltgalvis, Kristen A; Call, Jarrod A; Cochrane, Gregory D et al. (2012) Exercise training improves plantar flexor muscle function in mdx mice. Med Sci Sports Exerc 44:1671-9
Spangenburg, Espen E; Geiger, Paige C; Leinwand, Leslie A et al. (2012) Regulation of physiological and metabolic function of muscle by female sex steroids. Med Sci Sports Exerc 44:1653-62

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