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.
Highlights
Duchenne muscular dystrophy (DMD) is an X-linked recessive disease which affects 1 in every 3500 boys resulting in progressive muscle atrophy, loss of ambulation and cardio-respiratory failure (Levi et al, 2015)
Our data confirm that a, b, and DT-tubulin are elevated with muscular dystrophy and extend these findings to show that eliminating Nox2 ROS production in mdx mice prevents the increase in all three forms of tubulin (Figure 1B–D)
Because DT-tubulin is the de-tyrosinated form of a-tubulin, and both DT- and a-tubulin are elevated in mdx muscle, we assessed the fraction of a-tubulin that is de-tyrosinated
Summary
Duchenne muscular dystrophy (DMD) is an X-linked recessive disease which affects 1 in every 3500 boys resulting in progressive muscle atrophy, loss of ambulation and cardio-respiratory failure (Levi et al, 2015). Nox ROS is upregulated early (19 d; (Whitehead et al, 2010)), prior to changes in the MT network (Belanto et al, 2016; Iyer et al, 2017; Khairallah et al, 2012; Prins et al, 2009), and oxidation has been shown to be a post-translational modification of the MT network
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