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Reducing Early Atrophy with Leucine during Immobilization of Skeletal Muscle

Periodic Reporting for period 1 - REALISM (Reducing Early Atrophy with Leucine during Immobilization of Skeletal Muscle)

Reporting period: 2015-05-01 to 2017-04-30

Recovery from injury, illness, and/or disease is associated with periods of physical inactivity and skeletal muscle disuse (e.g. due to bed rest or cast-induced limb immobilization). The physical inactivity associated with periods of muscle disuse results in a loss of skeletal muscle mass, leading to negative health consequences including reductions in muscle strength, the onset of insulin resistance, a decline in basal metabolic rate, and the accumulation of bodyfat. These conditions are associated with pre-mature physical frailty, elevated health care costs, and an increased risk of mortality. Furthermore, muscle disuse forms a major health concern for the elderly who are already at an increased risk for sarcopenia, or the age-related loss of skeletal muscle mass and strength. In fact, episodic periods of muscle disuse that are common in the elderly (e.g. due to injury, illness, or disease) are now thought to represent periods of “catabolic crisis” that significantly accelerate the progression of sarcopenia. Currently, older adults (age 60 or >) make up the fastest growing age group, with projections that the elderly will represent ~21% of the global population by the year 2050. Although older adults are living longer, they are not living well. Population studies demonstrate that sarcopenia affects >20% of people age 60-70, and ~50% of people >75. Direct healthcare costs attributable to sarcopenia in the USA were ~$18.5 billion in the year 2000. Clearly, it is critical to identify strategies that can effectively offset the loss of muscle mass that occurs in response to muscle disuse in order to prevent an epidemic of frailty among the elderly.

The overall objectives of REALISM are as follows:
1. Identify whether MPB is elevated during the early (72 hours) stages of immobilization-induced disuse.
2. Identify whether leucine supplementation during this period of immobilization-induced disuse represents an effective nutritional intervention to attenuate MPB rates and preserve muscle mass.
3. Examine the impact of leucine supplementation on muscle mass and strength during 7 days of immobilization.
3. Identify whether cumulative MPS is reduced during the early (72 hours) stages of immobilization-induced disuse in the elderly.
4. Identify whether leucine supplementation during this period of immobilization-induced disuse represents an effective nutritional intervention to attenuate decline in cumulative MPS rates and preserve muscle mass in the elderly.

The results from REALISM will identify the mechanisms underlying disuse-induced muscle atrophy in response to immobilization and examine potential therapeutic strategies to offset the loss of muscle mass and strength in younger and older adults.
"To date we have made substantial progress towards completing the REALISM project. Since the beginning of the project, we have completed the following:

1) Obtained Ethics Approval for Work Packages #1, #2, and #3.
2) Recruited all subjects required for Work Packages #1, #2, and #3. In total we recruited 48 subjects (12 young females; 12 young males; 12 older females; 12 older males).
3) Collected all data required for Work Packages #1, #2, and #3 and completed Milestone #1, #2, #3, #7, #8, #12, #13. Data collection included dual-energy X-ray absorptiometry (DEXA) and computed tomography (CT) scans and biological samples including saliva, blood, and skeletal muscle tissue. To provide an indication of the volume of work undertaken, the REALISM project involved obtaining a total of 240 skeletal muscle biopsy samples across the 3 work packages.

We are currently in the process of completing Milestone #4, #9, and #14 (completion of data analysis for Work Packages #1, #2, #3). When this is complete, we will be in a position to achieve Milestone #5, #6, #10, #11, #15, and #16 and Deliverable #1-7 which include research abstracts, peer reviewed publications, and a press release based on the project results generated from REALISM. As we are currently in the process of analyzing data, we do not yet have any results to provide on the REALISM project. However, following the first publication(s) resulting from REALISM we will contact the Press and Science Communications Department at Maastricht University to issue a “press release” to the local media to disseminate the results of REALISM in both in print (magazines, newspapers) and on-screen (television) since these are communication mediums commonly used the elderly. The aim of issuing a press release is to inform the target audience of the potential benefits of leucine supplementation as a non-pharmacological therapeutic strategy to preserve muscle mass during periods of physical inactivity. Another aim is to provide individuals with basic information on how to implement leucine supplementation in a practical ""real world"" setting, and to discuss it with their primary care physician to determine if it would be appropriate for them.

Many of the consequences of sarcopenia are predictive of public health burden, including physical frailty, admission to a long-term care facility, depression, hospitalization, and mortality. Disability is associated with an increased risk of hospitalization and nursing home placement, increased home healthcare costs and, obviously, health care expenditure. Given the effect of sarcopenia on disability, public healthcare costs of sarcopenia are high. For example, direct healthcare costs attributable to sarcopenia in the USA were ~$18.5 billion in the year 2000 (1). These costs were represented by hospitalization, nursing home admissions, and home healthcare expenditure (1). However, sarcopenia is also associated with several comorbidities such osteoporosis, obesity, and type II diabetes. If these comorbidities are included, the healthcare costs associated with sarcopenia would be substantially increased. Clearly sarcopenia represents an important public health challenge with broad socio-economic impact.

Identifying and implementing effective countermeasures to reduce disuse-induced muscle loss in health and aging is important given the growing number of older persons affected by sarcopenia and its disabling complications. Identifying and targeting the determinants of muscle loss in health and aging is a necessary first step to limit the impact of sarcopenia on public health. The results from REALISM will identify the underlying changes in MPS and MPB that accompany disuse-induced muscle loss. Furthermore, the results from REALISM will determine whether leucine supplementation co-ingested with each main meal represents an effective non pharmacological approach to maintain protein turnover and ultimately preserve skeletal muscle mass. If effective, leucine supplementation could represent an easily applicable nutrition-based lifestyle intervention, with an excellent safety profile, to help maintain muscle mass. Maintenance of muscle mass in aging may help older adults better maintain their independence and quality of life, thereby reducing healthcare burden.

1). Janssen I, Shepard DS, Katzmarzyk PT, Roubenoff R: The healthcare costs of sarcopenia in the United States. J Am Geriatr Soc 2004, 52(1):80–85.