The purpose of our study was to compare two acquired
muscle atrophies and the use of
myostatin inhibition for their treatment.
Myostatin naturally inhibits skeletal muscle growth by binding to ActRIIB, a receptor on the cell surface of myofibers. Because blocking
myostatin in an adult wild-type mouse induces profound muscle
hypertrophy, we applied a soluble ActRIIB receptor to models of disuse (limb immobilization) and
denervation (sciatic nerve resection)
atrophy. We found that treatment of immobilized mice with ActRIIB prevented the loss of muscle mass observed in placebo-treated mice. Our results suggest that this protection from
disuse atrophy is regulated by serum and
glucocorticoid-induced
kinase (SGK) rather than by Akt.
Denervation atrophy, however, was not protected by ActRIIB treatment, yet resulted in an upregulation of the pro-
growth factors Akt, SGK and components of the mTOR pathway. We then treated the denervated mice with the mTOR inhibitor
rapamycin and found that, despite a reduction in mTOR activation, there is no alteration of the
atrophy phenotype. Additionally,
rapamycin prevented the
denervation-induced upregulation of the
mTORC2 substrates Akt and SGK. Thus, our studies show that
denervation atrophy is not only independent from Akt, SGK and mTOR activation but also has a different underlying pathophysiological mechanism than
disuse atrophy.