Sarcopenia, the loss of muscle mass due to aging, causes or aggravates a range of debilitating conditions including coronary artery disease, obesity, type 2 diabetes, and frailty. Even though muscle mass is essential for health and quality of life, the molecular chain of events that lead from nutrition and activity to a change in muscle protein synthesis, mass and strength remains poorly understood. This study aims to examine critical factors that contribute to muscle strength, with the ultimate goal of improving the longevity and quality of life in millions of Americans. Specifically, we will look at the role playd by the primary leucine transporter in muscle, LAT1, in the development of sarcopenia. Since leucine uptake is required for the anabolic response to both resistance exercise and protein feeding, the objective of this work is to determine the role of LAT1 in anabolic resistance and develop a pharmacological strategy to maintain muscle mass and strength. Building on our previously published research in this area, and strong preliminary data, we have developed the working hypothesis that decreased mTOR activation and ribosome biogenesis in muscle results in anabolic resistance. We will test this hypothesis by examining these three specific aims: 1) Determine whether aging or loss of LAT1 imparts anabolic resistance to loading; 2) Determine whether loss of LAT1 imparts anabolic resistance to protein feeding; and 3) Determine whether increasing ribosome mass reverses anabolic resistance. This highly innovative proposal explores this essential question in muscle biology using novel techniques to measure ribosome biogenesis at multiple levels for the first time. The significance of this research is two-fold: 1)It will contribute to a basic understanding of the molecular events leading to sarcopenia, and 2) It will validate a simple drug treatment strategy that can increase muscle mass and thus improve quality of life and reduce mortality in the population. Successful completion of this application i one step towards the long-term objective of our laboratory: to create bigger, stronger, and more fatigue resistant muscles without the need for exercise.

Public Health Relevance

On average, we will lose 45% of our muscle mass and strength between our 20s and 80s and this process, called sarcopenia, increases our mortality. In 2000, it was estimated that the direct cost of sarcopenia in America was $18.5 billion and with the increasing number of older Americans, the economic costs of sarcopenia will escalate unless we can develop viable treatments. The simple pharmacological strategy proposed in this application, together with moderate exercise, could significantly decrease the number of Americans who suffer from sarcopenia and improve the quality of life of millions of people.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG045375-02
Application #
8878149
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Williams, John
Project Start
2014-07-01
Project End
2019-04-30
Budget Start
2015-05-01
Budget End
2016-04-30
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of California Davis
Department
Physiology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Baehr, Leslie M; West, Daniel W D; Marshall, Andrea G et al. (2017) Muscle-specific and age-related changes in protein synthesis and protein degradation in response to hindlimb unloading in rats. J Appl Physiol (1985) 122:1336-1350
Hodson, Nathan; Brown, Thomas; Joanisse, Sophie et al. (2017) Characterisation of L-Type Amino Acid Transporter 1 (LAT1) Expression in Human Skeletal Muscle by Immunofluorescent Microscopy. Nutrients 10:
Shaw, Gregory; Lee-Barthel, Ann; Ross, Megan Lr et al. (2017) Vitamin C-enriched gelatin supplementation before intermittent activity augments collagen synthesis. Am J Clin Nutr 105:136-143
Hughes, David C; Marcotte, George R; Marshall, Andrea G et al. (2017) Age-related Differences in Dystrophin: Impact on Force Transfer Proteins, Membrane Integrity, and Neuromuscular Junction Stability. J Gerontol A Biol Sci Med Sci 72:640-648
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Baehr, Leslie M; West, Daniel W D; Marcotte, George et al. (2016) Age-related deficits in skeletal muscle recovery following disuse are associated with neuromuscular junction instability and ER stress, not impaired protein synthesis. Aging (Albany NY) 8:127-46
Craig, Daniel M; Ashcroft, Stephen P; Belew, Micah Y et al. (2015) Utilizing small nutrient compounds as enhancers of exercise-induced mitochondrial biogenesis. Front Physiol 6:296
Philp, Andrew; Schenk, Simon; Perez-Schindler, Joaquin et al. (2015) Rapamycin does not prevent increases in myofibrillar or mitochondrial protein synthesis following endurance exercise. J Physiol 593:4275-84
Marcotte, George R; West, Daniel W D; Baar, Keith (2015) The molecular basis for load-induced skeletal muscle hypertrophy. Calcif Tissue Int 96:196-210

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