Atrophy resistance in human myotubes expressing high myostatin Grant uri icon

abstract

  • Muscle wasting, or cachexia, is a major risk factor for premature death affecting more than five million Americans. Currently, the only known effective therapeutic agent for the maintenance of muscle mass and prevention of cachexia is physical exercise. However, the mechanism(s) of this exercise effect is not fully understood. Myostatin, a hormone produced and secreted by skeletal muscle, has emerged as a potent regulator of muscle mass. Animals and humans lacking myostatin display more than two times the muscle mass of those with myostatin. Additionally, exposure to myostatin results in severe muscle wasting. Myostatin regulates muscle mass by activating SMAD2/3. These proteins affect muscle mass through two distinct mechansisms: 1) increasing expression of genes involved in protein degradation and 2) inhibiting Akt-induced protein synthesis. Myostatin activation of SMAD2/3 is inhibited by SMAD7. Both aerobic exercise and resistance training decrease circulating myostatin. This may be one mechanism by which exercise modulates muscle mass. We have identified primary human skeletal muscle cells that produce very high levels of myostatin. However, despite this elevated myostatin, these cells display normal rates of protein synthesis and breakdown. Additionally, these cells demonstrate a decreased response to atrophic stimuli. Due to the paradoxical relationship between high myostatin and decreased atrophic response, we have termed these cells HMAR (high myostatin, atrophy resistant). Interestingly, in addition to high levels of myostatin, we have found that HMAR cells express high levels of SMAD7. These HMAR cells provide a unique model to examine the mechanisms by which myostatin regulates muscle mass. In this project, we propose the novel hypothesis that HMAR cells are insensitive to myostatin. We believe that myostatin insensitivity in these cells prevents activation of SMAD2/3, maintaining normal basal rates of protein synthesis and degradation and decreased response to atrophic stimuli. Furthermore, we hypothesize that overproduction of SMAD7 is responsible for the myostatin insensitivity observed in HMAR cells. In order to test these hypotheses, we propose stimulating control and HMAR cells with exogenous MSTN. We will measure overall protein synthesis, degradation, and SMAD2/3 activity. Additionally, we will perform genetic knockdown of SMAD7 followed by MSTN exposure to determine whether SMAD7 is responsible for MSTN insensitivity in HMAR cells. The goals of the proposed project are to 1) increase the scientific knowledge regarding the role of myostatin in regulating muscle mass, 2) provide a unique training opportunity for the doctoral student, and 3) identify protential therapeutic targets for myostatin inhibition.

date/time interval

  • July 2012 - June 2013