Identifying Therapeutic Targets of Accelerated Sarcopenia
Condition: Sarcopenia; Diabetes Mellitus; Aging
MeSH terms: Sarcopenia
Study type: Interventional

Summary: 
      The proposed research is designed to identify the mechanisms that can accelerate loss of
      muscle size, strength and physical function in type 2 diabetes and with hospitalization in
      older persons. About ⅓ of older Americans have type 2 diabetes, and about ⅓ of the
      hospitalizations in the USA involve persons older than 65 year of age. The proposed research
      is relevant to the part of NIH's mission that pertains to development of the fundamental
      knowledge that will improve health and reduce the burdens of disability, because this work
      will provide the fundamental evidence to identify new targets for the development of
      innovative treatments to slow down muscle loss and disability in our aging society.
    

Detailed description: 
      Sarcopenia is a major contributor to frailty and increases the risk of falls, physical
      dependence, disability and mortality in older adults. It advances slowly with healthy aging.
      However, diseases or other insults and injuries can accelerate sarcopenia and lead to
      catastrophic declines in mobility and independence. For example, chronic diseases such as
      Type 2 Diabetes Mellitus (T2DM) are associated with accelerated loss of muscle mass and
      function in seniors; hospitalization with bed rest inactivity acutely accelerates sarcopenia.
      What it is not know is how concurrent diseases, inactivity or other insults and injuries
      accelerate sarcopenia in older adults. This knowledge gap hinders the development of
      innovative, targeted treatments for this disabling condition. The objective of this research
      is to examine the basic mechanisms that underlie accelerated sarcopenia in older adults and
      identify potential targets for interventions. The central hypothesis is that a global and
      fundamental mechanism of acute or chronic acceleration of sarcopenia is a reduction in
      skeletal muscle amino acid transport, which decreases muscle protein anabolism, and can be
      reversed by activation of the mammalian/mechanistic Target of Rapamycin Complex 1 (mTORC1)
      signaling with a non-amino acid stimulus, such as exercise. Amino acid transport is an active
      process that controls intracellular amino acid availability and the activation of protein
      synthesis in skeletal muscle. It is regulated by amino acid concentrations and non-amino acid
      stimuli that activate mTORC1 signaling, such as resistance exercise and insulin.The central
      hypothesis will be tested with the following specific aims: 1) Determine the effect of T2DM
      on the sensitivity of skeletal muscle amino acid transport to dietary amino acids. 2)
      Determine the effect of short-term bed rest inactivity on the sensitivity of skeletal muscle
      amino acid transport to dietary amino acids. 3) Determine the effect of resistance exercise
      on the sensitivity of amino acid transport to dietary amino acids in acute and chronic
      accelerated sarcopenia induced by inactivity or T2DM. Amino acid transport and protein
      metabolism in muscle will be measured using integrative molecular, imaging and stable isotope
      methodologies, identifying specific upstream regulators involved in the anabolic resistance
      of accelerated sarcopenia that can be targeted with novel treatments to reduce sarcopenia and
      improve independence in older adults.
    

Intervention name(s): Resistance exercise training; Bed rest; Intensive physical therapy
Intervention type(s): Behavioral; Behavioral; Behavioral
Intervention description(s): Supervised resistance exercise training, 3 times a week for 3 months; Bed rest for 5 days, followed by standard rehabilitation for 2 days; Intensive weight bearing PT, daily, during bed rest
Other intervention name(s): RT; BR; PT
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Basic Science
Keywords: exercise; bed rest; muscle; nutrition; amino acids