1a. Objectives (from AD-416)
1. Investigate the nutritional and activity-related mediators of skeletal muscle atrophy associated with advancing age in animal and human studies. 2. Evaluate the chronic effects of dietary proteins/amino acids and physical activity/inactivity on changes in skeletal muscle structure and function and physical functioning in at-risk older individuals.
1b. Approach (from AD-416)
Sarcopenia, the age-associated loss in skeletal muscle mass, is a contributing factor to the observed declines in physiological capacity and functional performance with advancing age. The economic impact of sarcopenia has been estimated at $18.5 billion, annually. The overall theme of this project will be to use a platform based approach in the identification, evaluation, and understanding of nutritional and physical activity interventions that possess anabolic properties in skeletal muscle and have the potential to prevent or reverse impaired motor performance and/or physical dysfunction in older individuals. Using our well characterized rodent model of human sarcopenia, we propose to examine the mechanisms and efficacy of nutrient modulation on overload-induced skeletal muscle hypertrophy. We then propose to perform parallel clinical studies to examine the influence of physical activity/exercise and nutrition on the control of muscle protein turnover in older adults with defined low muscle mass and functional limitations. We will also evaluate the chronic effects of dietary protein/amino acids and physical activity/inactivity on changes in skeletal muscle structure and function and physical functioning in at risk older adults. Finally, we will examine the effects of a multi-modal physical activity program on changes in muscle mass, strength, physical functioning, and disability in older individuals with clinically demonstrated functional limitations. The unique pairing of clinical studies examining the influence of protein nutrition and physical activity on sarcopenia with basic approaches that identify the molecular landscape and potential targets in skeletal muscle for preventive interventions (nutritional, physical activity) may accelerate our ability to translate these findings to aging people.
3. Progress Report
Our project, Nutrition, Physical Activity, and Sarcopenia in the Elderly, has made significant progress on all objective outlined in our project plan. In the current project year, we have fully or substantially met the majority of our approved milestones. The two milestones that were not met were due to our lack of ability to secure extramural funding to support the muscle performance ancillary study to the Lifestyle Interventions for Independence in the Elderly (LIFE) study. Work on both objective 1 (Investigate the nutritional and activity-related mediators of skeletal muscle atrophy associated with advancing age in animal and human studies) and objective 2 (Evaluate the chronic effects of dietary proteins/amino acids and physical activity/inactivity on changes in skeletal muscle structure and function and physical functioning in at-risk older individuals) is ongoing. Studies under subobjective 1a (Determine the mechanisms and efficacy of nutrient modulation on overload-induced skeletal muscle hypertrophy) are all in progress. Work is presently examining the influence of dietary factors on skeletal muscle growth capacity in older animals and specifically the influence of fat accumulation in skeletal muscle on this process. We have also completed studies of muscle growth capacity in young and older humans as part of subobjective 1b (Perform parallel clinical studies to determine the influence of physical activity/exercise and nutrition on the control of muscle growth in older adults with defined low muscle mass and functional limitations). The human studies have revealed that metabolic signals related to stimulation of skeletal muscle protein synthesis are blunted in older adults and this response may be mediated by increases in skeletal muscle content of ceramides (a biologically active lipid). Once these studies have been completed, we may embark in a new direction and examine dietary lipids (saturated vs. unsaturated fatty acids) on ceramide accumulation in skeletal muscle to understand how these factors may influence growth capacity in muscle. Work on the proposed studies under Subobjective 2a. (Determine the efficacy of selected nutritional and lifestyle behaviors on age-related changes in skeletal muscle physiology and physical functioning) is underway. A key feature of these studies is our approach to study populations of older adults who are at increased risk for the development of late life disability. Our randomized study examining the influence of 40 g per day supplement of whey protein and changes in muscle mass, strength, physical performance in older men and women with mobility limitations has been completed and we are in the process of cleaning and analyzing the data. In addition, recruitment for the Lifestyle Interventions for Independence in the Elderly (LIFE) study will be completed by December 2011. A total of 1600 older men and women (200 at HNRCA Field Center) will be recruited at 8 field centers to examine whether a structured program of physical activity will prevent the development of late life disability in at risk older adults.
1. Regulators of lipid (fat) synthesis are increased in aging skeletal muscle. With advancing age, several reports have noted an increase in the content of triglyceride (fat) in skeletal muscle. This increase in muscle triglyceride has been associated with the development of insulin resistance, elevated risk of Type II diabetes, and may be related to skeletal muscle growth capacity. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, found that not only is skeletal muscle triglyceride increased with advancing age but several of the major regulators (genes and proteins) of triglyceride synthesis are also increased. These results suggest that age-associated triglyceride accumulation in skeletal muscle is an active process that is driven by increased biosynthetic capacity for lipid synthesis. These results may lead to the development of specific targets to alter insulin resistance and enhance muscle growth capacity that are directed at regulators of lipid synthesis in muscle.
2. Increases in bioactive lipids alter anabolic signaling in aging humans It is well established that an increased accumulation of lipids and their various metabolites within skeletal muscle are directly related to reductions in insulin-stimulated glucose uptake (insulin resistance). However, far less is known about their role in the control of skeletal muscle protein turnover and anabolic signaling. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, found that following a single strength training exercise session, young men had a significant increase in several growth-activating proteins in their muscle while these proteins were unchanged in the muscle of older men following a similar exercise session. They also observed increases in several lipids in muscle, including ceramides, diacylglycerol, and acylcarnitines, from the older men but not the younger men. These results suggest that the accumulation of specific lipids (ceramides, diacylglycerols, and acylcarnitines) in muscle with advancing age may play a role in the development of sarcopenia.