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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • March 23, 2021

Published In

Volume / Issue

  • 22 / 6

Start / End Page

  • 3252 -

PubMed ID

  • 33806917

Pubmed Central ID

  • PMC8005132

Electronic International Standard Serial Number (EISSN)

  • 1422-0067

International Standard Serial Number (ISSN)

  • 1422-0067

Digital Object Identifier (DOI)

  • 10.3390/ijms22063252

Language

  • eng