Sarcopenia, the age-related loss of muscle mass and strength, is a major health concern that contributes to the onset of frailty. Frailty and sarcopenia are major predictors of mortality, poor prognoses and loss of independence. Most importantly, the older adult with sarcopenia and/or frailty has a diminished quality of life. Identifying interventions that prevent, attenuate, and/or reverse the loss of muscle mass and strength will have a significant impact on improving the quality of life, both for basic activities of daily livig and recreational pursuits. The long-term goal of my research is to establish interventions for sarcopenia and frailty. The working hypothesis is that sarcopenia interventions will restore functional ability and extend healthspan. In preliminary work, using a cross-sectional cohort of mice to characterize age-related declines in functional and physiological ability, we developed a Neuromuscular Healthspan Scoring System to evaluate potential treatments. The next step is to test an intervention for sarcopenia. Resistance exercise is a well-accepted treatment for sarcopenia. Hence, the hypothesis for the proposed research is that resistance training will result in improved physical function, strength, and healthspan. This hypothesis will be tested with two Specific Aims: (1) Develop a resistance training model for mice and (2) Determine the effects of a resistance exercise training protocol on functional performance, muscle contractility, muscle remodeling and cellular mechanisms contributing to hypertrophy in adult, old, and aged mice. The main mechanisms to be examined include activation of the PI3k Akt mTORC1 pathway and satellite cell proliferation. The proposed studies use current technologies and approaches including mass spectrometry, single skeletal muscle fiber physiology, whole muscle physiology, and immunohistochemistry. Both mentors for this proposal, Drs. Thompson and Ferrington, are well-established scientists in the fields of aging, muscle, biochemistry and proteomics, have a strong history of successful mentorship, collaborations, funding and are well published. An advisory team, composed of experts in the fields of statistics, aging, proteomics, myogenic precursor cell biology, translational research and exercise physiology, will provide critical scientific guidance and career advice. The training program is tailored to meet my career goals by providing opportunities to enhance my scientific skill set, interact with established scientists, attend and present at national meetings, write and publish scientific papers, and mentor an undergraduate student. Lastly, the laboratories of my mentors and collaborators, the core facilities and Centers within the Medical School, and at the University of Minnesota will provide an exceptional environment for my training. I am firmly committed to studying aging in my career and will be seeking a post-doctoral position-- ultimately leading to a tenured academic appointment and becoming principle investigator of a lab at a research university. Receiving this F31 NRSA Fellowship will be a significant step towards my future success.

Public Health Relevance

Sarcopenia, the age-related loss of skeletal muscle mass and strength, can ultimately cause the elderly to lose their independence and contribute to the onset of frailty-costing society multi- billions of dollars ($18.5 billion in direct healthcare costs in 000) and decreasing the quality of life of our senior citizens (Jannsen, et al. 2004). It is in the best interest of society, both financially and as a healthspan improvement issue, to find successful interventions for this muscle wasting condition. The overall research focus surrounding this training program is to investigate the effects of aging on skeletal muscle and to develop strategies to mitigate the effects of sarcopenia.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F10B-S (20))
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Williams, John
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University of Minnesota Twin Cities
Physical Medicine & Rehab
Schools of Medicine
United States
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Graber, Ted G; Kim, Jong-Hee; Grange, Robert W et al. (2015) C57BL/6 life span study: age-related declines in muscle power production and contractile velocity. Age (Dordr) 37:9773
Graber, Ted G; Ferguson-Stegall, Lisa; Liu, Haiming et al. (2015) Voluntary Aerobic Exercise Reverses Frailty in Old Mice. J Gerontol A Biol Sci Med Sci 70:1045-58
Liu, Haiming; Graber, Ted G; Ferguson-Stegall, Lisa et al. (2014) Clinically relevant frailty index for mice. J Gerontol A Biol Sci Med Sci 69:1485-91
Chen, Chiao-Nan Joyce; Graber, Ted G; Bratten, Wendy M et al. (2014) Immunoproteasome in animal models of Duchenne muscular dystrophy. J Muscle Res Cell Motil 35:191-201