Redox Biology & Cell Signaling Laboratory, Department of Health and Kinesiology, Graduate Faculty of Nutrition, Texas A&M University, College Station, TX 77843, USA.
Department of Molecular Physiology & Biophysics, University of Iowa, Iowa City, IA 52242, USA.
Int J Mol Sci. 2021 Mar 23;22(6):3252. doi: 10.3390/ijms22063252.
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.
在机械卸载（例如，太空飞行和卧床休息）期间，应激反应不足和氧化应激升高可导致骨骼肌萎缩。热休克蛋白（例如，HSP70）、抗氧化酶和肌膜神经元型一氧化氮合酶（nNOS）的波动与卸载诱导的萎缩有关。我们最近发现，在卸载过程中，肌膜 NADPH 氧化酶-2 复合物（Nox2）升高，这是血管紧张素 II 受体 1 的下游事件，与萎缩同时发生。在这里，我们假设 Nox2 的肽抑制会减轻卸载过程中 HSP70、MnSOD 和肌膜 nNOS 的破坏，从而防止肌肉纤维萎缩。F344 大鼠分为对照组（CON）、后肢卸载组（HU）和后肢卸载+7.5mg/kg/天 gp91ds-tat 组（HUG）。gp91ds-tat 减轻了 Nox2 亚基 p67phox 阳性染色在卸载诱导中的升高。HU 肌肉中 HSP70 蛋白丰度显著降低，但 HUG 肌肉中没有。MnSOD 随卸载而减少；然而，gp91ds-tat 并没有挽救 MnSOD。相比之下，Nox2 抑制可防止 Nrf2 等抗氧化转录因子因卸载而被抑制。HU 抑制了 nNOS 的生物活性，而 Nox2 抑制则消除了这一作用。Nox2 抑制显著减轻了 gp91ds-tat 对后肢卸载引起的比目鱼肌纤维萎缩的作用。这些数据确立了 Nox2 在卸载诱导的肌肉萎缩中的因果作用，与 HSP70、Nrf2 和肌膜 nNOS 的保存有关。
