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NADPH oxidase mediates microtubule alterations and diaphragm dysfunction in dystrophic mice.

ABSTRACT: Skeletal muscle from mdx mice is characterized by increased Nox2 ROS, altered microtubule network, increased muscle stiffness, and decreased muscle/respiratory function. While microtubule de-tyrosination has been suggested to increase stiffness and Nox2 ROS production in isolated single myofibers, its role in altering tissue stiffness and muscle function has not been established. Because Nox2 ROS production is upregulated prior to microtubule network alterations and ROS affect microtubule formation, we investigated the role of Nox2 ROS in diaphragm tissue microtubule organization, stiffness and muscle/respiratory function. Eliminating Nox2 ROS prevents microtubule disorganization and reduces fibrosis and muscle stiffness in mdx diaphragm. Fibrosis accounts for the majority of variance in diaphragm stiffness and decreased function, implicating altered extracellular matrix and not microtubule de-tyrosination as a modulator of diaphragm tissue function. Ultimately, inhibiting Nox2 ROS production increased force and respiratory function in dystrophic diaphragm, establishing Nox2 as a potential therapeutic target in Duchenne muscular dystrophy.

SUBMITTER: Loehr JA

PROVIDER: S-EPMC5812717 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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NADPH oxidase mediates microtubule alterations and diaphragm dysfunction in dystrophic mice.

Loehr James Anthony JA Wang Shang S Cully Tanya R TR Pal Rituraj R Larina Irina V IV Larin Kirill V KV Rodney George G GG

eLife 20180130

Skeletal muscle from <i>mdx</i> mice is characterized by increased Nox2 ROS, altered microtubule network, increased muscle stiffness, and decreased muscle/respiratory function. While microtubule de-tyrosination has been suggested to increase stiffness and Nox2 ROS production in isolated single myofibers, its role in altering tissue stiffness and muscle function has not been established. Because Nox2 ROS production is upregulated prior to microtubule network alterations and ROS affect microtubule ...[more]

PMID: 29381135

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Project description:Background and aimsResistin has been implicated in cardiovascular disease and poor interventional cardiovascular outcomes. Previous studies by our group demonstrated resistin promoted vascular smooth muscle cell (VSMC) migration through protein kinase C epsilon (PKCε) pathways, while few others showed that resistin induced reactive oxygen species (ROS) generation in various cell types. In this study, we aim to systemically examine the functional role of resistin at the cellular and tissue levels as well as the potential mechanistic relationship between resistin-induced PKCε activation and ROS production.MethodsPlasma collected from patients undergoing carotid interventions was analyzed for resistin level and ROS. VSMCs were treated with resistin in the presence or absence of PKCε and NADPH oxidase (Nox)-specific inhibitors. Intracellular ROS production was analyzed using confocal microscopy and Nox activity with chemiluminescence. In vivo studies were performed in apolipoprotein E knock out (ApoE-/-) mice to determine therapeutic effects of PKCε-specific inhibitor, using the guide-wire injury model.ResultsWe observed significant correlation between plasma resistin and circulating levels of oxidative stress in patients with severe atherosclerotic disease. We also demonstrated that resistin induced ROS production via PKCε-mediated Nox activation. Resistin-induced ROS production was time-dependent, and Nox4 was the primary isoform involved. Inhibition of Nox completely abolished resistin-exaggerated VSMC proliferation, migration and dedifferentiation, as well as pro-inflammatory cytokine release. Upstream modulation of PKCε significantly reduced resistin-mediated cytosolic ROS, Nox activity and VSMC dysfunction. Moreover, PKCε-specific inhibitor mitigated resistin-induced Nox activation and intimal hyperplasia in ApoE-/- mice.ConclusionsResistin-associated VSMC dysfunction and intimal hyperplasia are related to PKCε-dependent Nox activation and ROS generation. Targeting the PKCε-Nox pathway may represent a novel strategy in managing resistin-associated atherosclerotic complications.

Dataset Information

NADPH oxidase mediates microtubule alterations and diaphragm dysfunction in dystrophic mice.

Publications

NADPH oxidase mediates microtubule alterations and diaphragm dysfunction in dystrophic mice.

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