Effect of EUK-134 on Akt-mTOR signaling in the rat soleus during 7 days of mechanical unloading

Abstract

Mechanical unloading stimulates rapid changes in skeletal muscle morphology, characterized by atrophy of muscle fiber cross-sectional area (CSA) and a partial fiber-type shift from slow to fast-twitch. Recent studies revealed that oxidative stress contributes to activation of FoxO3a, proteolytic signaling and unloading-induced muscle atrophy via translocation of the mu-splice variant of neuronal nitric oxide synthase (nNOSμ) and activation of FoxO3a. Yet, there is limited understanding of the role of reactive oxygen species (ROS) on the Akt-mTOR pathway signaling during unloading. We hypothesized that EUK-134, a mimetic of the antioxidant enzymes superoxide dismutase and catalase would protect Akt-mTOR signaling in the unloaded rat soleus. Male Fischer-344 rats were separated into three study groups: ambulatory control (CON, n = 11), 7 days of hindlimb unloading + saline injections (HU, n = 11), or 7 days of HU + superoxide dismutase/catalase mimetic EUK-134; (HU+EUK-134, n = 9). EUK-134 mitigated unloading-induced dephosphorylation of Akt, as well as FoxO3a, in the soleus. mTOR phosphorylation in the EUK-treated unloaded rats was not different than controls. However, EUK-134 did not significantly rescue p70S6K phosphorylation. EUK-134 attenuated translocation of nNOSμ from the membrane to the cytosol, reduced nitration of tyrosine residues, and suppressed upregulation of caveolin-3 and dysferlin. EUK-134 ameliorated HU-induced remodeling: atrophy of muscle fibers and the 12% increase in type II MHC positive fibers. Attenuation of the unloaded muscle phenotype was associated with decreased ROS, as assessed by ethidium+ nuclei. We conclude that oxidative stress affects Akt-mTOR signaling in unloaded skeletal muscle. Direct linkage of abrogation of nNOSμ translocation with Akt-mTOR signaling during unloading is the subject of future investigation.

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