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Article

Nox2 Inhibition Regulates Stress Response and Mitigates Skeletal Muscle Fiber Atrophy during Simulated Microgravity

1
Redox Biology & Cell Signaling Laboratory, Department of Health and Kinesiology, Graduate Faculty of Nutrition, Texas A&M University, College Station, TX 77843, USA
2
Department of Molecular Physiology & Biophysics, University of Iowa, Iowa City, IA 52242, USA
3
Brigham & Women’s Hospital, Harvard Medical School, Cambridge, MA 02115, USA
4
Department of Kinesiology, University of Texas Rio Grande Valley, Harlingen, TX 78539, USA
5
Department of Cellular and Molecular Biology, Federal University of Paraíba, João Pessoa, Paraíba 58059900, Brazil
6
School of Medicine, University of North Carolina, Chapel Hill, NC 27516, USA
7
Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Daniela Grimm
Int. J. Mol. Sci. 2021, 22(6), 3252; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063252
Received: 24 February 2021 / Revised: 12 March 2021 / Accepted: 16 March 2021 / Published: 23 March 2021
(This article belongs to the Special Issue Microgravity and Space Medicine)
Insufficient stress response and elevated oxidative stress can contribute to skeletal muscle atrophy during mechanical unloading (e.g., spaceflight and bedrest). Perturbations in heat shock proteins (e.g., HSP70), antioxidant enzymes, and sarcolemmal neuronal nitric oxidase synthase (nNOS) have been linked to unloading-induced atrophy. We recently discovered that the sarcolemmal NADPH oxidase-2 complex (Nox2) is elevated during unloading, downstream of angiotensin II receptor 1, and concomitant with atrophy. Here, we hypothesized that peptidyl inhibition of Nox2 would attenuate disruption of HSP70, MnSOD, and sarcolemmal nNOS during unloading, and thus muscle fiber atrophy. F344 rats were divided into control (CON), hindlimb unloaded (HU), and hindlimb unloaded +7.5 mg/kg/day gp91ds-tat (HUG) groups. Unloading-induced elevation of the Nox2 subunit p67phox-positive staining was mitigated by gp91ds-tat. HSP70 protein abundance was significantly lower in HU muscles, but not HUG. MnSOD decreased with unloading; however, MnSOD was not rescued by gp91ds-tat. In contrast, Nox2 inhibition protected against unloading suppression of the antioxidant transcription factor Nrf2. nNOS bioactivity was reduced by HU, an effect abrogated by Nox2 inhibition. Unloading-induced soleus fiber atrophy was significantly attenuated by gp91ds-tat. These data establish a causal role for Nox2 in unloading-induced muscle atrophy, linked to preservation of HSP70, Nrf2, and sarcolemmal nNOS. View Full-Text
Keywords: NADPH oxidase; oxidative stress; unloading; atrophy; skeletal muscle; HSP70; MnSOD; Nrf2; nNOS NADPH oxidase; oxidative stress; unloading; atrophy; skeletal muscle; HSP70; MnSOD; Nrf2; nNOS
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MDPI and ACS Style

Lawler, J.M.; Hord, J.M.; Ryan, P.; Holly, D.; Janini Gomes, M.; Rodriguez, D.; Guzzoni, V.; Garcia-Villatoro, E.; Green, C.; Lee, Y.; Little, S.; Garcia, M.; Hill, L.; Brooks, M.-C.; Lawler, M.S.; Keys, N.; Mohajeri, A.; Kamal, K.Y. Nox2 Inhibition Regulates Stress Response and Mitigates Skeletal Muscle Fiber Atrophy during Simulated Microgravity. Int. J. Mol. Sci. 2021, 22, 3252. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063252

AMA Style

Lawler JM, Hord JM, Ryan P, Holly D, Janini Gomes M, Rodriguez D, Guzzoni V, Garcia-Villatoro E, Green C, Lee Y, Little S, Garcia M, Hill L, Brooks M-C, Lawler MS, Keys N, Mohajeri A, Kamal KY. Nox2 Inhibition Regulates Stress Response and Mitigates Skeletal Muscle Fiber Atrophy during Simulated Microgravity. International Journal of Molecular Sciences. 2021; 22(6):3252. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063252

Chicago/Turabian Style

Lawler, John M., Jeffrey M. Hord, Pat Ryan, Dylan Holly, Mariana Janini Gomes, Dinah Rodriguez, Vinicius Guzzoni, Erika Garcia-Villatoro, Chase Green, Yang Lee, Sarah Little, Marcela Garcia, Lorrie Hill, Mary-Catherine Brooks, Matthew S. Lawler, Nicolette Keys, Amin Mohajeri, and Khaled Y. Kamal. 2021. "Nox2 Inhibition Regulates Stress Response and Mitigates Skeletal Muscle Fiber Atrophy during Simulated Microgravity" International Journal of Molecular Sciences 22, no. 6: 3252. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063252

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