Nutrient Sensing & Signaling in Aging Muscle
Condition: Nutrient Sensing
Study type: Interventional

Summary: 
      This research seeks to better understand how cellular and molecular bases of changes
      associated with aging contribute to decreased function and increased incidence of disease.
      Specific mechanism in muscle responsible for anabolic resistance - a key component of
      sarcopenia and frailty - will be identified. The proposed research is relevant to public
      health because the discovery of new targets for interventions and novel therapeutics to
      improve muscle strength and function, prevent falls, and reduce physical dependency will
      improve the healthspan and quality of life in older adults by improving their physical
      function and ability to remain independent and healthy for a longer period of time.
    

Detailed description: 
      Anabolic resistance to nutrition is the reduced ability of skeletal muscle to increase
      protein synthesis in response to feeding. It is a major contributor to muscle atrophy in
      aging, inactivity, burns, trauma, and cancer cachexia. The effects of anabolic resistance on
      health and physical function are important. For example, the loss of muscle mass and strength
      with aging (sarcopenia) increases the risk for falls, physical dependency and morbidity in
      older adults. A major determinant of muscle size is muscle protein content, which is
      controlled by the fine balance between protein synthesis and breakdown. Recently,
      investigators have found that amino acids and exercise independently increase muscle protein
      synthesis and overall anabolism by activating the mammalian/mechanistic target of rapamycin
      complex 1 (mTORC1) signaling pathway in humans. Aging and inactivity reduce these anabolic
      effects, but the underlying mechanisms of anabolic resistance are not known. The purpose of
      this application is to better understand how anabolic resistance develops in skeletal muscle.
      The long-term goal is to identify specific molecular targets for the development of
      evidence-based clinical interventions to counteract anabolic resistance and muscle wasting in
      clinical populations. Here, investigators will focus on one potential mechanisms underlying
      anabolic resistance to amino acids: activation of mTORC1 in human muscle cells. The central
      hypothesis is that the physical activity restores mTORC1 signaling which is the primary
      contributor to anabolic resistance in human skeletal muscle. Investigators will test this
      hypothesis in healthy subjects with the following specific aim: Determine the effect of
      increasing habitual physical activity on anabolic resistance. Investigators will study human
      subjects utilizing stable isotopes model to measure amino acid kinetics and muscle protein
      metabolism in combination with molecular analysis of muscle to determine the regulatory role
      of amino acids, physical inactivity, and amino acid transporter functional activity on
      mTORC1. The proposed approach is innovative because it represents a new and substantial
      departure from the status quo as investigators will examine the underlying mechanisms of
      anabolic resistance to nutrition using novel methodological approaches. The proposed research
      is significant because it will lead to the development of evidence-based interventions to
      treat sarcopenia and muscle wasting.
    

Intervention name(s): Exercise
Intervention type(s): Behavioral
Intervention description(s): Progressive resistance exercise training
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Nutrient Sensing; Exercise; Elderly