PMID- 29315934 OWN - NLM STAT- MEDLINE DCOM- 20190212 LR - 20211204 IS - 1469-445X (Electronic) IS - 0958-0670 (Linking) VI - 103 IP - 4 DP - 2018 Apr 1 TI - Effect of Eukarion-134 on Akt-mTOR signalling in the rat soleus during 7 days of mechanical unloading. PG - 545-558 LID - 10.1113/EP086649 [doi] AB - NEW FINDINGS: What is the central question of this study? Translocation of nNOSmu 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 nNOSmu, 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 nNOSmu 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 mu-splice variant of neuronal nitric oxide synthase (nNOSmu) 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); 7 days of hindlimb unloading + saline injections (HU, n = 11); or 7 days 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 nNOSmu 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 nNOSmu translocation with Akt-mTOR signalling during unloading is the subject of future investigation. CI - (c) 2018 The Authors. Experimental Physiology (c) 2018 The Physiological Society. FAU - Kuczmarski, J Matthew AU - Kuczmarski JM AD - Redox Biology & Cell Signaling Laboratory, Department of Health and Kinesiology, Texas A&M University, College Station, TX, USA. AD - Heart and Vascular Institute, Penn State College of Medicine, Hershey, PA, USA. FAU - Hord, Jeff M AU - Hord JM AD - Redox Biology & Cell Signaling Laboratory, Department of Health and Kinesiology, Texas A&M University, College Station, TX, USA. FAU - Lee, Yang AU - Lee Y AD - Redox Biology & Cell Signaling Laboratory, Department of Health and Kinesiology, Texas A&M University, College Station, TX, USA. FAU - Guzzoni, Vinicius AU - Guzzoni V AD - Redox Biology & Cell Signaling Laboratory, Department of Health and Kinesiology, Texas A&M University, College Station, TX, USA. AD - Laboratory of Biochemistry and Molecular Biology, Department of Physiological Science, Federal University of Sao Carlos (UFSCar), Sao Carlos, SP, Brazil. FAU - Rodriguez, Dinah AU - Rodriguez D AD - Redox Biology & Cell Signaling Laboratory, Department of Health and Kinesiology, Texas A&M University, College Station, TX, USA. FAU - Lawler, Matthew S AU - Lawler MS AD - Redox Biology & Cell Signaling Laboratory, Department of Health and Kinesiology, Texas A&M University, College Station, TX, USA. AD - Department of Biomedical Engineering, Georgia Tech University, Atlanta, GA, USA. FAU - Garcia-Villatoro, Erika L AU - Garcia-Villatoro EL AD - Redox Biology & Cell Signaling Laboratory, Department of Health and Kinesiology, Texas A&M University, College Station, TX, USA. AD - Department of Nutrition and Food Science, Texas A&M University, College Station, TX, USA. FAU - Holly, Dylan AU - Holly D AD - Redox Biology & Cell Signaling Laboratory, Department of Health and Kinesiology, Texas A&M University, College Station, TX, USA. FAU - Ryan, Patrick AU - Ryan P AD - Redox Biology & Cell Signaling Laboratory, Department of Health and Kinesiology, Texas A&M University, College Station, TX, USA. FAU - Falcon, Kristian AU - Falcon K AD - Redox Biology & Cell Signaling Laboratory, Department of Health and Kinesiology, Texas A&M University, College Station, TX, USA. FAU - Garcia, Marcela AU - Garcia M AD - Redox Biology & Cell Signaling Laboratory, Department of Health and Kinesiology, Texas A&M University, College Station, TX, USA. FAU - Janini Gomes, Mariana AU - Janini Gomes M AD - Physiopathology Program in Internal Medicine, Botucatu Medical School, Sao Paulo State University (UNESP), Botucatu, SP, Brazil. FAU - Fluckey, James D AU - Fluckey JD AD - Muscle Biology Laboratory, Department of Health and Kinesiology, Texas A&M University, College Station, TX, USA. FAU - Lawler, John M AU - Lawler JM AD - Redox Biology & Cell Signaling Laboratory, Department of Health and Kinesiology, Texas A&M University, College Station, TX, USA. AD - Department of Nutrition and Food Science, Texas A&M University, College Station, TX, USA. LA - eng GR - S10 RR022532/RR/NCRR NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20180228 PL - England TA - Exp Physiol JT - Experimental physiology JID - 9002940 RN - 0 (Antioxidants) RN - 0 (Forkhead Box Protein O3) RN - 0 (Muscle Proteins) RN - EC 1.11.1.6 (Catalase) RN - EC 1.15.1.1 (Superoxide Dismutase) RN - EC 2.7.1.1 (mTOR protein, rat) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Antioxidants/*pharmacology MH - Catalase/metabolism MH - Forkhead Box Protein O3/metabolism MH - Hindlimb Suspension/*physiology MH - Male MH - Muscle Fibers, Fast-Twitch/drug effects/metabolism MH - Muscle Fibers, Slow-Twitch/drug effects/metabolism MH - Muscle Proteins/metabolism MH - Muscle, Skeletal/*drug effects/*metabolism MH - Oxidative Stress/drug effects MH - Proto-Oncogene Proteins c-akt/*metabolism MH - Rats MH - Rats, Inbred F344 MH - Signal Transduction/*drug effects MH - Superoxide Dismutase/metabolism MH - TOR Serine-Threonine Kinases/*metabolism OTO - NOTNLM OT - Akt OT - atrophy OT - hindlimb unloading OT - mTOR OT - neuronal nitric oxide synthase OT - oxidative stress OT - p70S6K OT - reactive oxygen species OT - skeletal muscle EDAT- 2018/01/10 06:00 MHDA- 2019/02/13 06:00 CRDT- 2018/01/10 06:00 PHST- 2017/08/18 00:00 [received] PHST- 2018/01/02 00:00 [accepted] PHST- 2018/01/10 06:00 [pubmed] PHST- 2019/02/13 06:00 [medline] PHST- 2018/01/10 06:00 [entrez] AID - 10.1113/EP086649 [doi] PST - ppublish SO - Exp Physiol. 2018 Apr 1;103(4):545-558. doi: 10.1113/EP086649. Epub 2018 Feb 28.