Â© 2018 The Authors. Experimental Physiology Â© 2018 The Physiological Society New Findings: What is the central question of this study? Translocation of nNOSÎ¼ 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 Aktâ€“mTOR pathway? What is the main finding and its importance? Eukarion-134 rescued Aktâ€“mTOR signalling and sarcolemmal nNOSÎ¼, 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 nNOSÎ¼ 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 Î¼-splice variant of neuronal nitric oxide synthase (nNOSÎ¼) and activation of FoxO3a. There is limited understanding of the role of reactive oxygen species in the Aktâ€“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 Aktâ€“mTOR signalling in the unloaded rat soleus. Male Fischer 344 rats were separated into the following three study groups: ambulatory control (nÂ =Â 11); 7Â days of hindlimb unloadingÂ + saline injections (HU, nÂ =Â 11); or 7Â days of HU + EUK-134; (HUÂ +Â EUK-134, nÂ =Â 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 nNOSÎ¼ 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 Aktâ€“mTOR signalling in unloaded skeletal muscle. Direct linkage of abrogation of nNOSÎ¼ translocation with Aktâ€“mTOR signalling during unloading is the subject of future investigation.
- Neuronal Nitric Oxide Synthase
- Skeletal Muscle
- Hindlimb Unloading
- Oxidative Stress
- Reactive Oxygen Species