Effect of Eukarion-134 on Akt-mTOR signalling in the rat soleus during 7days of mechanical unloading.
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NEW FINDINGS: What is the central question of this study? Translocation of nNOS initiates catabolic signalling via FoxO3a and skeletal muscle atrophy during mechanical unloading. Recent evidence suggests that unloading-induced muscle atrophy and FoxO3a activation are redox sensitive. Will a mimetic of superoxide dismutase and catalase (i.e. Eukarion-134) also mitigate suppression of the Akt-mTOR pathway? What is the main finding and its importance? Eukarion-134 rescued Akt-mTOR signalling and sarcolemmal nNOS, which were linked to protection against the unloading phenotype, muscle fibre atrophy and partial fibre-type shift from slow to fast twitch. The loss of nNOS from the sarcolemma appears crucial to Akt phosphorylation and is redox sensitive, although the mechanisms remain unresolved. ABSTRACT: Mechanical unloading stimulates rapid changes in skeletal muscle morphology, characterized by atrophy of muscle fibre cross-sectional area and a partial fibre-type shift from slow to fast twitch. Recent studies revealed that oxidative stress contributes to activation of forkhead box O3a (FoxO3a), proteolytic signalling and unloading-induced muscle atrophy via translocation of the -splice variant of neuronal nitric oxide synthase (nNOS) and activation of FoxO3a. There is limited understanding of the role of reactive oxygen species in the Akt-mammalian target of rapamycin (mTOR) pathway signalling during unloading. We hypothesized that Eukarion-134 (EUK-134), a mimetic of the antioxidant enzymes superoxide dismutase and catalase, would protect Akt-mTOR signalling in the unloaded rat soleus. Male Fischer 344 rats were separated into the following three study groups: ambulatory control (n=11); 7days of hindlimb unloading+ saline injections (HU, n=11); or 7days of HU + EUK-134; (HU+EUK-134, n=9). EUK-134 mitigated unloading-induced dephosphorylation of Akt, as well as FoxO3a, in the soleus. Phosphorylation of mTOR in the EUK-treated HU rats was not different from that in control animals. However, EUK-134 did not significantly rescue p70S6K phosphorylation. EUK-134 attenuated translocation of nNOS from the membrane to the cytosol, reduced nitration of tyrosine residues and suppressed upregulation of caveolin-3 and dysferlin. EUK-134 ameliorated HU-induced remodelling, atrophy of muscle fibres and the 12% increase in type II myosin heavy chain-positive fibres. Attenuation of the unloaded muscle phenotype was associated with decreased reactive oxygen species, as assessed by ethidium-positive nuclei. We conclude that oxidative stress affects Akt-mTOR signalling in unloaded skeletal muscle. Direct linkage of abrogation of nNOS translocation with Akt-mTOR signalling during unloading is the subject of future investigation.
Kuczmarski, J. M., Hord, J. M., Lee, Y., Guzzoni, V., Rodriguez, D., Lawler, M. S., ... Lawler, J. M.
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12
complete list of authors
Kuczmarski, J Matthew||Hord, Jeff M||Lee, Yang||Guzzoni, Vinicius||Rodriguez, Dinah||Lawler, Matthew S||Garcia-Villatoro, Erika L||Holly, Dylan||Ryan, Patrick||Falcon, Kristian||Garcia, Marcela||Janini Gomes, Mariana||Fluckey, James D||Lawler, John M
