Nutritional and Contractile Regulation of Muscle Growth

Skeletal muscle comprises about 40% of one's body weight and contains about 50% to 75% of
all the proteins in the human body. The turnover of protein is a regular process in the
human body. In healthy adults, the interplay between muscle protein synthesis and muscle
protein breakdown results in no net growth or loss of muscle mass. But when the scale tips
towards muscle protein breakdown, muscle wasting can occur. This can result in negative
consequences, because not only does muscle fill the obvious role of converting chemical
energy into mechanical energy for moving and maintaining posture, but muscle is also
involved in the following less apparent roles: regulating metabolism; removing potentially
toxic substances from blood circulation; producing fuel for other tissues; storing energy
and nitrogen, both of which are important for fueling the brain and immune system; and
facilitating wound healing during malnutrition, starvation, injury, and disease. Therefore,
muscle is important not only for physical independence but also for mere survival of the
human body. In fact, a mere 30% loss of the body's proteins results in impaired respiration
and circulation and can eventually lead to death. The purpose of this study is to examine
the physiological and cellular mechanisms that regulate skeletal muscle growth. Results from
the study may help to develop future treatments for maintaining and possibly increasing
muscle mass as a way to improve function, reduce disease complications, and increase
survival.

This study will enroll healthy participants who will be randomly assigned to one of several
treatment arms within one of three separate experiments. Overall, the three experiments will
examine the following: (1) whether the mammalian target of rapamycin (mTOR) signaling
pathway--a group of molecules that work together to control a specific cellular function--is
responsible for stimulating muscle protein synthesis after resistance exercise and/or
ingestion of an amino acid supplement; (2) whether restricting blood flow with a blood
pressure cuff during low-intensity resistance exercise ultimately leads to muscle protein
synthesis; and (3) whether aging is associated with reduced physiological and cellular
mechanisms that are related to muscle protein synthesis and whether such a reduction can be
overcome by post-exercise ingestion of an amino acid supplement or blood flow restriction
during low-intensity resistance exercise.

Depending on which treatment arm participants are assigned to, they may receive amino acid
supplementation, the drug rapamycin, the drug sodium nitroprusside, and/or placebo. They may
also undergo high-intensity resistance exercise, low-intensity resistance exercise, or
low-intensity resistance exercise along with blood flow restriction. All participants will
attend a single 8-hour study visit and a follow-up visit 1 week later. During the study
visit, participants will undergo the following: measurements of vital signs, height, and
weight; blood and urine sampling; a dual energy x-ray absorptiometry (DEXA) scan; and an
infusion study that will include additional blood sampling, muscle biopsies, and assigned
interventions. The follow-up visit will include evaluation of any incisions that were made
during the infusion study.

Inclusion Criteria:

- 18 to 35 years of age for the young groups

- 60 to 85 years of age for the older groups

- In the follicular phase for the young women participants

- Ability to sign consent form, as based on a score of greater than 25 on the 30-item
Mini Mental State Examination (MMSE)

- Stable body weight for at least 1 year

Exclusion Criteria:

- Physical dependence or frailty, as determined by impairment in any of the activities
of daily living (ADLs), history of more than two falls per year, or significant
weight loss in the past year

- Exercise training that consists of more than two weekly sessions of moderate to high
intensity aerobic or resistance exercise

- Significant heart, liver, kidney, blood, or respiratory disease

- Peripheral vascular disease

- Diabetes mellitus or other untreated endocrine disease

- Active cancer

- History of cancer for participants who may be randomly assigned to rapamycin)

- Acute infectious disease or history of chronic infections (e.g., tuberculosis,
hepatitis, HIV, herpes)

- Treatment with anabolic steroids or corticosteroids within 6 months of study entry

- Alcohol or drug abuse

- Tobacco use (smoking or chewing)

- Malnutrition (e.g., body mass index [BMI] less than 20 kg/m2, hypoalbuminemia, and/or
hypotransferrinemia)

- Obesity (BMI greater than 30 kg/m2)

- Lower than normal hemoglobin levels