Nutritional and Contractile Regulation of Muscle Growth
Condition: Sarcopenia
MeSH terms: Sarcopenia
Study type: Interventional
Phase: Phase 1

Summary: 
      Muscle wasting, which involves the loss of muscle tissue, is common in many conditions, such
      as cancer, AIDS, trauma, kidney failure, bone fracture, and sepsis. It is also prevalent
      among the elderly and in people who experience periods of physical inactivity and
      weightlessness. Muscle wasting can lead to overall weakness, immobility, physical dependence,
      and a greater risk of death when exposed to infection, surgery, or trauma. There is a need to
      develop scientifically based treatments that prevent muscle wasting. As one step towards such
      a goal, this study will examine the physiological and cellular mechanisms that regulate
      skeletal muscle growth.
    

Detailed description: 
      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.
    

Intervention name(s): Rapamycin; Amino acid supplementation; Low-intensity resistance exercise; Sodium nitroprusside; Blood flow restriction cuff; Low-intensity resistance exercise
Intervention type(s): Drug; Other; Other; Drug; Device; Other
Intervention description(s): Single 16-mg oral dose; Nutritional drink containing essential amino acids; Leg extension exercises on a Cybex leg extension machine; Variable rate for 3 hours; Blood flow restriction for 5 minutes after the second biopsy; Leg extension exercises on a Cybex leg extension machine
Other intervention name(s): KAATSU cuff
Intervention MeSH terms: Sirolimus; Nitroprusside
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: Sarcopenia; Aging; Metabolism; Muscle; mTOR; Essential Amino Acids; Exercise; Rapamycin